New fluorous tagging and scavenging reactants and methods of synthesis and use thereof

ABSTRACT

The present invention includes methods and compositions for increasing the fluorous nature of an organic compound by reacting it with at least one fluorous compound to produce a fluorous tagged organic compound. The increased fluorous nature of the fluorous tagged organic compound can then be utilized to separate the fluorous organic compound from untagged reagents, reactants, catalysts and/or products derived therefrom. The resultant fluorous tagged organic compound can be subjected to subsequent chemical transformations, wherein the fluorous nature of the tagged compound is utilized to increase the ease of separation of the fluorous tagged organic compound from untagged reagents, reactants, catalysts and/or products derived therefrom, after each chemical transformation. The chemical transformations result in a second fluorous tagged organic compound wherein the fluorous nature of the second fluorous tagged organic compound can then be reduced by removing the fluorous group therefrom, thereby producing a second organic compound that may be employed as a pharmaceutical compound or intermediate, or a combinatorial library component.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional PatentApplication Serial No. 60/395,067, entitled “New Fluorous Tagging(Scavenging) Reactants and Methods of Synthesis and Use Thereof”, filedJul. 11, 2002; U.S. Provisional Patent Application Serial No.60/396,952, entitled “New Fluorous Tagging Reagents and Methods ofSynthesis and Use Thereof”, filed Jul. 18, 2002; U.S. Provisional PatentApplication Serial No. 60/442,712, entitled “Fluorous Synthesis ofDisubstituted Pyrimidines”, filed Jan. 27, 2003; U.S. Provisional PatentApplication Serial No. 60/442,762, entitled “FluoMar™, A FluorousVersion of the Marshall Resin for Solution-phase Library Synthesis”,filed Jan. 27, 2003; and U.S. Provisional Patent Application Serial No.60/442,840, entitled “Fluorous Electrophilic Scavengers for SolutionPhase Parallel Synthesis”, filed Jan. 27, 2003, which are incorporatedby reference herein in their entirety.

GOVERNMENTAL INTEREST

[0002] This invention was made with Government support under grants 1R44 GM67326-01 and 1 R43 GM066415-01 awarded by the National Institutesof Health. The Government may have certain rights in the invention.

FIELD OF THE INVENTION

[0003] The present invention relates to fluorous tagging compounds andfluorous scavenging compounds and to methods of increasing the fluorousnature of organic compounds by reacting them with a fluorous tagging orscavenging compound.

BACKGROUND OF THE INVENTION

[0004] It is generally the case that organic compounds must besynthesized as pure substances through well-planned reactions andscrupulous separation/purification. In fields such as drug discovery,catalyst design and new material development, tens of thousands oforganic compounds must be synthesized and tested to discover a fewactive ones. In the pharmaceutical industry, for example, synthesizinglarge numbers of compounds in the traditional way is ineffectiverelative to the rapid emergence of new biological targets. A majorfactor limiting the productivity of orthodox solution (liquid) phaseorganic synthesis is the time consuming process of purification. Highthroughput organic synthesis, therefore, preferably integrates organicreactions with rapid purification/separation procedures.

[0005] The attachment of “tags” to organic reaction components hasbecome commonplace in combinatorial and parallel high throughputsyntheses to facilitate the separation process. See, for example,Curran, D. P. “Strategy-level Separations in Organic Synthesis; FromPlanning to Practice,” Angew. Chem., Int. Ed. Eng. 1998, 37, 1175-1196;Flynn, D. “Phase-trafficking Reagents and Phase-switching Strategies forParallel Synthesis,” Med. Res. Rev. 1999, 19, 408-432. The process oftagging excess reagents, reactants, catalysts or byproducts for theirseparation from the desired products is often called “scavenging” or“quenching”. In a common embodiment of tagging, a substrate, for examplea small organic molecule, is tagged with a separation tag typicallycomprised of a polymeric bead in a technique known as “solid phasesynthesis”. See, for example, Seneci, P. “Solid-phase Synthesis andCombinatorial Technologies,” John Wiley and Sons New York, 2000.Conducting one or more reactions on the tagged substrate (or subsequentintermediates) with untagged reagents, reactants, catalysts, etc. thenprovides a tagged product. The presence of the separation tag allowseasy separation of the tagged intermediates and/or product from untaggedreagents, reactants, catalysts and/or products derived therefrom. Forexample, simple filtration is usually used to separate the polymer beadtagged intermediate or product from solvent, byproduct and/or anyunreacted reagent.

[0006] Because reactions with polymer-bound substrates and intermediatesare typically heterogeneous, large excesses of reagents are often neededto drive reactions to completion. This adds to the expense of a reactionand can also lead to unwanted tagged byproducts. Even when usingexcesses of reagents, solid phase synthesis methods often do not matchtheir solution phase counterparts in terms of speed, yield, scope andcleanliness of products. Furthermore, other than by filtration, it isnot usually possible to further purify polymer-bound intermediates andproducts. In other words, polymer bound intermediates or products cannotbe separated from bound byproducts without removal from the polymer andsubsequent purification. Accordingly reactions on the solid phase thatoccur with broad scope in quantitative yield (so that no polymer-boundbyproducts are formed) are the target of much research.

[0007] In a common embodiment of scavenging, a solution phase reactionis conducted under standard conditions, and then a scavenger or quencheris added and allowed to react with one or more reaction components thathave been targeted for separation from the desired products. The mostcommonly used scavengers are solid-phase materials such as polymers orbonded phases of silica. See, for example, Kaldor, S. W., Siegel, M. G.“Combinatorial Chemistry Using Polymer Supported Reagents,” Curr. Opin.Chem. Bio. 1997, 1, 101-106; Shuttleworth, S. J., Allin, S. M., Sharma,P. K. “Functionalised Polymers: Recent Developments and New Applicationsin Synthetic Organic Chemistry,” Synthesis 1997, 1217-1239; Ley, S. V.,et al. “Multi-step Organic Synthesis Using Solid-supported Reagents andScavengers: A New Paradigm in Chemical Library Generation,” J. Chem.Soc., Perkin Trans. 1 2000, 3815-4195; Eames, J., Watkinson, M.“Polymeric Scavenger Reagents in Organic Synthesis,” Eur. J. Org. Chem.2001, 1213-1224.

[0008] Like reactions with polymer-bound substrates, reactions withsolid phase scavengers are almost always heterogeneous. Large excessesof solid phase scavengers are often used to facilitate the scavengingreaction, yet the speed and cleanliness of solution phase reactionsstill often cannot be duplicated. Solution phase scavengers withappropriate acid or basic functionality can be used, but this approachrequires that the desired products be acid or base stable (or both) andlimits the functionality that can be present.

[0009] Recently, fluorous synthetic and separation techniques haveattracted the interests of organic chemists. In fluorous synthetictechniques, reaction components are typically attached to fluorousgroups such as perfluoroalkyl groups to facilitate the separation ofproducts. Reactions are carried out in the solution phase, so solubilityand reaction problems inherent with solid phase synthetic techniques donot arise. In general, fluorous tagged or scavenged molecules partitionpreferentially into a fluorous phase while non-tagged/non-scavengedmolecules partition into an organic phase. Although fluorous syntheticand/or separation techniques are promising, such techniques arecurrently limited by a lack of available and suitable fluorous tags andscavengers.

[0010] Accordingly, further improvements would be a welcome addition tothe art, wherein fluorous tagging and scavenging compounds, and methodsfor their synthesis and use in increasing the fluorous nature of organiccompounds are developed.

SUMMARY OF THE INVENTION

[0011] The present invention includes methods and compositions forincreasing the fluorous nature of an organic compound by reacting itwith at least one fluorous compound to produce a fluorous tagged organiccompound. The increased fluorous nature of the fluorous tagged organiccompound can then be utilized to separate the fluorous organic compoundfrom untagged reagents, reactants, catalysts and/or products derivedtherefrom. The resultant fluorous tagged organic compound can besubjected to subsequent chemical transformations, wherein the fluorousnature of the tagged compound is utilized to increase the ease ofseparation of the fluorous tagged organic compound from untaggedreagents, reactants, catalysts and/or products derived therefrom, aftereach chemical transformation. The chemical transformations result in asecond fluorous tagged organic compound wherein the fluorous nature ofthe second fluorous tagged organic compound can then be reduced byremoving the fluorous group therefrom, thereby producing a secondorganic compound that may be employed as a pharmaceutical compound orintermediate, or a combinatorial library component.

[0012] In one embodiment, the present invention provides a method forincreasing the fluorous nature of an organic compound by reacting theorganic compound with at least one second compound having the formula:

X—CR¹R²—C₆H_(5-m)—[W_(p)(CH₂)_(n)R_(f)]_(m)  (I)

[0013] R_(f) is a fluorous group. The group X on fluorous compound (I)is either a leaving group, a nucleophilic group or an electrophilicgroup. The substitutents R¹ and R² are independently, the same ordifferent, either hydrogen, a linear alkyl group, a branched alkylgroup, a phenyl group, a substituted phenyl group having the structureC₆H_(5-q)(W′)_(q), or fluorous substituted phenyl groups having thestructure of either C₆H_(5-m′)[W_(p′)(CH₂)_(n′)R_(f)]_(m′) orC₆H_(5-m″)[W_(p″)(CH₂)_(n″)R_(f)]_(m″). The integer values for m, m′ andm″ are from 1 to 5; the integer values for n, n′, and n″ are from 0 to5; p, p′, and p″ have values of either 0 or 1; and q has an integervalue from 0 to 5. W is an atom or a grouping of atoms having thestructure O, S, NR³, CR⁴R⁵, or SiR⁶R⁷, wherein when W is SiR⁶R⁷ and R¹and R² are each hydrogen, X is not one of Br, N-imidazolyl or —OH. W′ isa grouping of atoms having the structure OR⁸, SR⁹, NR¹⁰R¹¹, CR¹²R¹³R¹⁴,or SiR¹⁵R¹⁶R¹⁷. The substituents R³, R⁴, R⁵, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³,and R¹⁴ are independently, the same or different, either hydrogen,linear alkyl, branched alkyl, aryl, benzyl or —CH₂)_(n′)R_(f), and thesubstituents R⁶, R⁷, R¹⁵, R¹⁶, and R¹⁷ are independently, the same ordifferent, either linear alkyl, branched alkyl, aryl, benzyl or—(CH₂)_(n′″)R_(f), wherein n′″ in an integer from 0 to 5.

[0014] The organic compound has at least one functional group thatreacts with group X on at least one second fluorous compound (I) to format least one chemical bond between the organic compound and at least onesecond compound. The chemical reaction results in a first fluoroustagged organic compound with an increased fluorous nature relative tothe fluorous nature of the organic compound. The increased fluorousnature of the first fluorous tagged organic compound enables separatingthe first fluorous tagged organic compound from other compounds by useof a fluorous separation technique.

[0015] In a second embodiment, the present invention provides a methodfor increasing the fluorous nature of an organic compound by reactingthe organic compound with at least one second compound having theformula:

XCO₂CH₂R_(d)  (II)

[0016] wherein X is a leaving group and R_(d) has one of the followingsubstructures:

[0017] a) —CH═CH—(CH₂)_(n)R_(f),

[0018] c) —C₆H_(5-m″)[W_(p)(CH₂)_(n)R_(f)]_(m″).

[0019] R_(f) and R_(f′) are each fluorous groups. The integer value form is from 1 to 4, m′ is an integer from 0 to 4, and m″ is an integerfrom 1 to 5. The integer values for n and n′ are each from 0 to 5 and pand p′ each has a value of either 0 or 1. W and W′ are atoms orgroupings of atoms each having the possible structure of O, S, NR²⁵,CR²⁶R²⁷, or SiR²⁸R²⁹. The substituents R²⁵, R²⁶ and R²⁷ areindependently, the same or different, either hydrogen, linear alkyl,branched alkyl, aryl, benzyl or —CH₂)_(n)R_(f), and the substituents R²⁸and R²⁹ are independently, the same or different, either linear alkyl,branched alkyl, aryl, benzyl or —(CH₂)_(n)R_(f).

[0020] The organic compound has at least one functional group thatreacts with leaving group X on at least one second fluorous compound(II) to form at least one chemical bond between the organic compound andat least one second compound. The chemical reaction results in a firstfluorous tagged organic compound with an increased fluorous naturerelative to the fluorous nature of the organic compound. The increasedfluorous nature of the first fluorous tagged organic compound enablesseparating the first fluorous tagged organic compound from othercompounds by use of a fluorous separation technique.

[0021] In another embodiment, the present invention provides a methodfor increasing the fluorous nature of an organic compound by reactingthe organic compound with at least one second compound having theformula:

R³¹R³²N(CH₁₂)_(n)R_(f)  (III)

[0022] wherein R_(f) is a fluorous group and n is an integer with avalue from 0 to 5. R⁻R⁼, when taken together, can comprise any of thegroups:

[0023] a) —(CH₂)_(m)W(CH₂)_(m′)—,

[0024] forming a cyclic amine. Alternatively, R³¹ and R³² canindependently comprise any of the following groups: alkyl and pyridyl,hydrogen and —CH₂)_(n″)NH₂, hydrogen and —(CH₂)_(n″)N[(CH₂)_(n″)NH₂]₂,or —CH₂)_(n′″)OH, and —(CH₂)_(n″″)OH forming an acyclic amine. Theinteger values for m and m′ are each from 2 to 4, m″ and m′″ each haveinteger values from 0 to 3, and m″″ is an integer from 0 to 4. Theinteger value for n′ is from 0 to 5 and n″, n′″ and n″″ each haveinteger values from 1 to 5. The value of p is either 0 or 1. W is anatom or grouping of atoms having the structure of CH₂, O, S, NH, orNR³³, wherein R³³ is either a linear alkyl, a branched alkyl or a benzylgroup, and W′ is an atom or grouping of atoms having the structure O, S,NR³⁴, CR³⁵R³⁶, or SiR³⁷R³⁸, wherein R³⁴, R³⁵, and R³⁶ are independently,the same or different, either hydrogen, linear alkyl, branched alkyl,aryl, benzyl or —(CH₂)_(n)R_(f), and R³⁷ and R³⁸ are independently, thesame or different, either linear alkyl, branched alkyl, aryl, benzyl or—(CH₂)_(n)R_(f).

[0025] The organic compound has at least one functional group thatreacts with at least one N or —OH group on at least one second compound(III) to form at least one chemical bond between the organic compoundand at least one second compound, where the chemical bond may be eitherionic or covalent. The chemical reaction results in a first fluoroustagged organic compound with an increased fluorous nature relative tothe fluorous nature of the organic compound. The increased fluorousnature of the first fluorous tagged organic compound enables separatingthe first fluorous tagged organic compound from other compounds by useof a fluorous separation technique.

[0026] In still another embodiment, the present invention provides amethod for increasing the fluorous nature of an organic compound byreacting the organic compound with at least one second compound havingthe formula:

X—C₆H_(5-m)—[W_(p)(CH₂)_(n)R_(f)]_(m)  (IV)

[0027] wherein R_(f) is a fluorous group, m has an integer value from 1to 5, n has an integer value from 0 to 5, p is either 0 or 1 and W is anatom or grouping of atoms having the structure of O, S, NR³⁹, CR⁴⁰R⁴¹,or SiR⁴²R⁴³. When W is O, then X can have the structure —SO₂NHNH₂, —CHOwhen p is 1, —SH, —(CH₂)_(n′)SH, —C(═NR^(B))C₆H₄Y, —C(═O)CH₂C(═O)R⁴⁴,—COCl, —SO₂Cl, —OH, —NCZ, or —SO₃H. When W is S, NR³⁹, CR⁴⁰R⁴¹, orSiR⁴²R⁴³, then X can have the structure —SO₂NH₂, —SO₂NHNH₂, —CHO when pis 1, —SH, CH₂)_(n′)SH, —C(═NR^(B))C₆H₄Y, —C(═O)CH₂C(═O)R⁴⁴, —COCl,—SO₂Cl, —OH, —NCZ, or —SO₃H. Z is either oxygen or sulfur. Y is eitheran electron withdrawing group, a hydrogen or an alkyl group and R^(B) iseither hydrogen, an alkyl group, an aryl group or a hydroxyl group. Theinteger value of n′ is from 2 to 5. R³⁹, R⁴⁰ and R⁴¹ are independently,the same or different, either hydrogen, linear alkyl, branched alkyl,aryl, benzyl or —(CH₂)_(n)R_(f), and R⁴² and R⁴³ are independently, thesame or different, either linear alkyl, branched alkyl, aryl, benzyl or—(CH₂)_(n)R_(f). R⁴⁴ is either linear alkyl, branched alkyl or benzyl.

[0028] The organic compound has at least one functional group thatreacts with group X on at least one second compound (IV) to form atleast one chemical bond between the organic compound and at least onesecond compound. The chemical reaction results in a first fluoroustagged organic compound with an increased fluorous nature relative tothe fluorous nature of the organic compound. The increased fluorousnature of the first fluorous tagged organic compound enables separatingthe first fluorous tagged organic compound from other compounds by useof a fluorous separation technique.

[0029] In a further embodiment, the present invention provides a methodfor increasing the fluorous nature of an organic compound by reactingthe organic compound with at least one second compound having theformula:

X—(CH₂)_(n)R_(f)  (V)

[0030] wherein R_(f) is a fluorous group and n is an integer from 0 to5. X is a grouping of atoms having the substructure of either—C(CH₃)₂COCl, —CR⁴⁵R⁴⁶SH, —CR⁴⁵R⁴⁶SR⁴⁷, —SO₂Cl, —OC(═O)NHNH₂,—NHC(═NH)NH₂, —SO₂NH₂, —SO₂NHNH₂, —NCZ, -maleimide, -succinic anhydride,or —COCH₂COR⁴⁸. R⁴⁵, R⁴⁶, R⁴⁷, and R⁴⁸ are independently, the same ordifferent, either hydrogen, linear alkyl, branched alkyl, benzyl, or—(CH₂)_(n)R_(f) and Z is either oxygen or sulfur.

[0031] The organic compound has at least one functional group thatreacts with group X on at least one second compound (V) to form at leastone chemical bond between the organic compound and at least one secondcompound. The chemical reaction results in a first fluorous taggedorganic compound with an increased fluorous nature relative to thefluorous nature of the organic compound. The increased fluorous natureof the first fluorous tagged organic compound enables separating thefirst fluorous tagged organic compound from other compounds by use of afluorous separation technique.

[0032] In still a further embodiment, the present invention provides acompound having the formula:

X—CR¹R²—C₆H_(5-m)—[W_(p)(CH₂)_(n)R_(f)]_(m)  (I)

[0033] R_(f) is a fluorous group. The group X is either a leaving group,a nucleophilic group or an Electrophilic group. The substitutents R¹ andR² are independently, the same or different, either hydrogen, a linearalkyl group, a branched alkyl group, a phenyl group, a substitutedphenyl group having the structure C₆H_(5-q)(W′)_(q), or fluoroussubstituted phenyl groups having the structure of eitherC₆H_(5-m′)[W_(p′)(CH₂)_(n′)R_(f)]_(m′) orC₆H_(5-m″)[W_(p″)(CH₂)_(n″)R_(f)]_(m″). The integer values for m, m′ andm″ are from 1 to 5; the integer values for n, n′, and n″ are from 0 to5; p, p′, and p″ have values of either 0 or 1; and q has an integervalue from 0 to 5. W is an atom or a grouping of atoms having thestructure O, S, NR³, CR⁴R⁵, or SiR⁶R⁷, wherein when W is SiR⁶R⁷ and R¹and R² are each hydrogen, X is not one of Br, N-imidazolyl or —OH. W′ isa grouping of atoms having the structure OR⁸, SR⁹, NR¹⁰R¹¹, CR¹²R¹³R¹⁴,or SiR¹⁵R¹⁶R¹⁷. The substituents R³, R⁴, R⁵, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³,and R¹⁴ are independently, the same or different, either hydrogen,linear alkyl, branched alkyl, aryl, benzyl or —(CH₂)_(n′″)R_(f), and thesubstituents R⁶, R⁷, R¹⁵, R¹⁶, and R¹⁷ are independently, the same ordifferent, either linear alkyl, branched alkyl, aryl, benzyl or—(CH₂)_(n′″)R_(f), wherein n′″ in an integer from 0 to 5.

[0034] In yet a further embodiment, the present invention provides acompound having the formula:

XCO₂CH₂R_(d)  (II)

[0035] wherein X is a leaving group and Rd has one of the followingsubstructures:

[0036] a) —CH═CH—(CH₂)_(n)R_(f),

[0037] c) —C₆H_(5-m″)[W_(p)(CH₂)_(n)R_(f)]_(m″).

[0038] R_(f) and R_(f′) are each fluorous groups. The integer value form is from 1 to 4, m′ is an integer from 0 to 4, and m″ is an integerfrom 1 to 5. The integer values for n and n′ are each from 0 to 5 and pand p′ each has a value of either 0 or 1. W and W′ are atoms orgroupings of atoms each having the possible structure of O, S, NR²⁵,CR²⁶R²⁷, or SiR²⁸R²⁹. The substituents R²⁵, R²⁶ and R²⁷ areindependently, the same or different, either hydrogen, linear alkyl,branched alkyl, aryl, benzyl or —(CH₂)_(n)R_(f), and the substituentsR²⁸ and R²⁹ are independently, the same or different, either linearalkyl, branched alkyl, aryl, benzyl or —(CH₂)_(n)R_(f).

[0039] In yet another embodiment, the present invention provides acompound having the formula:

R³¹R³²N(CH₂)_(n)R_(f)  (III)

[0040] wherein R_(f) is a fluorous group and n is an integer with avalue from 0 to 5. R³¹R³², when taken together, comprise any of thegroups:

[0041] a) —(CH₂)_(m)W(CH₂)_(m′)—,

[0042] forming a cyclic amine. Alternatively, R³¹ and R³²,independently, can comprise any of the following groups: alkyl andpyridyl, hydrogen and —(CH₂)_(n″)NH₂, hydrogen and—(CH₂)_(n″)N[(CH₂)_(n″)NH₂]₂, or —(CH₂)_(n′″)OH, and —(CH₂)_(n″″)OHforming an acyclic amine. The integer values for m and m′ are each from2 to 4, m″ and m′″ each have integer values from 0 to 3, and m″″ is aninteger from 0 to 4. The integer value for n′ is from 0 to 5 and n″, n′″and n″″ each have integer values from 1 to 5. The value of p is either 0or 1. W is an atom or grouping of atoms having the structure of CH₂, O,S, NH, or NR³³, wherein R³³ is either a linear alkyl, a branched alkylor a benzyl group, and W′ is an atom or grouping of atoms having thestructure O, S, NR³⁴, CR³⁵R³⁶, or SiR³⁷R³⁸, wherein R³⁴, R³⁵, and R³⁶are independently, the same or different, either hydrogen, linear alkyl,branched alkyl, aryl, benzyl or —(CH₂)_(n)R_(f), and R³⁷ and R³⁸ areindependently, the same or different, either linear alkyl, branchedalkyl, aryl, benzyl or —(CH₂)_(n)R_(f).

[0043] In another embodiment, the present invention provides a compoundhaving the formula:

X—C₆H_(5-m)—[W_(p)(CH₂)_(n)R_(f)]_(m)  (IV)

[0044] wherein R_(f) is a fluorous group, m has an integer value from 1to 5, n has an integer value from 0 to 5, p is either 0 or 1 and W is anatom or grouping of atoms having the structure of O, S, NR³⁹, CR⁴⁰R⁴¹,or SiR⁴²R⁴³. When W is O, then X has the structure —SO₂NHNH₂, —CHO whenp is 1, —SH, —(CH₂)_(n′)SH, —C(═NR^(B))C₆H₄Y, or —C(═O)CH₂C(═O)R⁴⁴. WhenW is S, NR³⁹, CR⁴⁰R⁴¹, or SiR⁴²R⁴³, then X has the structure —SO₂NH₂,—SO₂NHNH₂, —CHO when p is 1, —SH, —(CH₂)_(n′)SH, —C(═NR^(B))C₆H₄Y, or—C(═O)CH₂C(═O)R⁴⁴. Z is either oxygen or sulfur. Y is either an electronwithdrawing group, a hydrogen or an alkyl group and R^(B) is a hydrogen,an alkyl group, an aryl group or a hydroxyl group. The integer value ofn′ is from 2 to 5. R³⁹, R⁴⁰ and R⁴¹ are independently, the same ordifferent, either hydrogen, linear alkyl, branched alkyl, aryl, benzylor —(CH₂)_(n)R_(f), and R⁴² and R⁴³ are independently, the same ordifferent, either linear alkyl, branched alkyl, aryl, benzyl or—(CH₂)_(n)R_(f). R⁴⁴ is linear alkyl, branched alkyl or benzyl.

[0045] In a further embodiment, the present invention provides acompound having the formula:

X—(CH₂)_(n)R_(f)  (V)

[0046] wherein R_(f) is a fluorous group and n is an integer from 0 to5. X is a grouping of atoms having the substructure of —C(CH₃)₂COCl.

[0047] In yet another embodiment, the present invention provides for acompound having a formula:

[0048] wherein R_(f), R_(f)′, and R_(f)″ are each fluorous groups,R_(f)′″ is a perfluoroalkyl group of 8 to 16 carbon atoms, X and X′ areleaving groups, m is an integer from 1 to 5, m′, m″, n, n′, and n″ areeach integers from 0 to 5, m′″ is an integer from 0 to 4, and p, p′, andp″ are each either 0 or 1. W, W′ and W″ are each an atom or groupingatoms having the formula O, S, NR⁴⁹, CR⁵⁰R⁵¹, or SiR⁵²R⁵³. R⁴⁹, R⁵⁰, andR⁵¹ are independently, the same or different, either hydrogen, linearalkyl, branched alkyl, aryl, benzyl or —(CH₂)_(n′″)R_(f). R⁵² and R⁵³are independently, the same or different, either hydrogen, linear alkyl,branched alkyl, aryl, benzyl or —(CH₂)_(n′″)R_(f) and n′″ is an integerfrom 0 to 5.

DETAILED DESCRIPTION OF THE INVENTION

[0049] Other than in the operating examples, or where otherwiseindicated, all numbers expressing quantities of ingredients, reactionconditions and so forth used in the specification and claims are to beunderstood as being modified in all instances by the term “about”.Accordingly, unless indicated to the contrary, the numerical parametersset forth in the following specification and attached claims areapproximations that may vary depending upon the desired propertiessought to be obtained by the present invention. At the very least, andnot as an attempt to limit the application of the doctrine ofequivalents to the scope of the claims, each numerical parameter shouldat least be construed in light of the number of reported significantdigits and by applying ordinary rounding techniques.

[0050] Notwithstanding that the numerical ranges and parameters settingforth the broad scope of the invention are approximations, the numericalvalues set forth in the specific examples are reported as precisely aspossible. Any numerical values, however, inherently contain certainerrors necessarily resulting from the standard deviation found in theirrespective testing measurements.

[0051] Also, it should be understood that any numerical range recitedherein is intended to include all sub-ranges subsumed therein. Forexample, a range of “1 to 10” is intended to include all sub-rangesbetween (and including) the recited minimum value of 1 and the recitedmaximum value of 10, that is, having a minimum value equal to or greaterthan 1 and a maximum value of equal to or less than 10.

[0052] Any patent, publication, or other disclosure material, in wholeor in part, that is said to be incorporated by reference herein isincorporated herein only to the extent that the incorporated materialdoes not conflict with existing definitions, statements, or otherdisclosure material set forth in this disclosure. As such, and to theextent necessary, the disclosure as set forth herein supersedes anyconflicting material incorporated herein by reference. Any material, orportion thereof, that is said to be incorporated by reference herein,but which conflicts with existing definitions, statements, or otherdisclosure material set forth herein will only be incorporated to theextent that no conflict arises between that incorporated material andthe existing disclosure material.

[0053] As used herein, the term “fluorous”, when used in connection withan organic (carbon-containing) molecule, moiety or group, refersgenerally to an organic molecule, moiety or group having a domain or aportion thereof rich in carbon-fluorine bonds (for example,fluorocarbons or perfluorocarbons, fluorohydrocarbons, fluorinatedethers, fluorinated amines and fluorinated adamantyl groups). Forexample, perfluorinated ether groups can have the general formula—[(CF₂)_(x)O(CF₂)_(y)]_(z)CF₃, wherein x, y and z are integers.Perfluorinated amine groups can, for example, have the general formula—[(CF₂)_(x)(NR^(a))CF₂)_(y)]_(z)CF₃, wherein R^(a) can, for example, be(CF₂)_(n)CF₃, wherein n is an integer. Fluorous ether groups andfluorous amine groups suitable for use in the present invention need notbe perfluorinated, however. The term “fluorous compound,” thus refers,generally, to a compound comprising a portion rich in carbon-fluorinebonds. As used herein, the term “perfluorocarbons” refers, generally, toorganic compounds in which all hydrogen atoms bonded to carbon atomshave been replaced by fluorine atoms. The terms “fluorohydrocarbons” and“hydrofluorocarbons” include organic compounds in which at least onehydrogen atom bonded to a carbon atom has been replaced by a fluorineatom. A few examples of suitable fluorous groups, R_(f), for use in thepresent invention include, but are not limited to, —C₄F₉, —C₆F₁₃,—C₈F₁₇, —C₁₀F₂₁, —C(CF₃)₂C₃F₇, —C₄F₈CF(CF₃)₂, —CF₂CF₂OCF₂CF₂OCF₃,—CF₂CF₂(NCF₂CF₃)CF₂CF₂CF₃, fluorous adamantly groups, and/or mixturesthereof.

[0054] Perfluoroalkyl groups and hydrofluoroalkyl groups are well suitedfor use in the present invention. For example, R_(f) can be a linearperfluoroalkyl group of 3 to 20 carbons, a branched perfluoroalkyl groupof 3 to 20 carbons, and a hydrofluoroalkyl group of 3 to 20 carbons.Hydrofluoroalkyl groups may typically include up to one hydrogen atomfor each two fluorine atoms. In the case of perfluoroalkyl groups andhydrofluoroalkyl groups, R_(f) may be a linear perfluoroalkyl group of 6to 12 carbons, a branched perfluoroalkyl group of 6 to 12 carbons, and ahydrofluoroalkyl group of 6 to 12 carbons.

[0055] The molecular weight of the fluorous tag of the present inventiontypically does not exceed about 2,500 g/mole, may be such as to notexceed 2,000 g/mole, and may be such as to not exceed 1,500 g/mole. Inaddition, compounds subject to the present invention may bear more thanone fluorous tag, each of which have the molecular weight as providedherein.

[0056] As used herein, the terms “tagging” and “scavenging” refer,generally, to attaching a fluorous moiety or group (referred to as a“fluorous tagging moiety”, “tagging group” or “fluorous tag”) to acompound to create a “fluorous tagged compound”. Separation of thetagged compounds of the present invention is achieved by using fluorousseparation techniques that are based upon differences between/among thefluorous nature of a mixture of compounds. As used herein, the term“fluorous separation technique” refers generally to a method that isused to separate mixtures containing fluorous molecules or organicmolecules bearing fluorous domains or tags from each other and/or fromnon-fluorous compounds based predominantly on differences in thefluorous nature of molecules (for example, size and/or structure of afluorous molecule or domain or the absence thereof). Fluorous separationtechniques include, but are not limited to, fluorous liquid-liquidextraction, fluorous solid phase extraction, and fluorouschromatography. See, for example, Danielson, N. D. et al.,“Fluoropolymers and Fluorocarbon Bonded Phases as Column Packings forLiquid Chromatography,” J. Chromat., 1991, 544, 187-199 ; Curran, D. P.“Fluorous Reverse Phase Silica Gel. A New Tool for PreparativeSeparations in Synthetic Organic and Organofluorine Chemistry,” Synlett,2001, 9, 1488; Curran D. P., “Fluorous Techniques for the Synthesis ofOrganic Molecules: A Unified Strategy for Reaction and Separation.” In:Stimulating Concepts in Chemistry (M. Shibasaki, J. Fraser Stoddart andF. Vögtle, eds.), Wiley-VCH, Weinheim, 2000, 25. Examples of suitablefluorocarbon bonded phases include, but are not limited to, FluoroFlash®columns commercially available from Fluorous Technologies Inc.(Pittsburgh, Pa.), Fluofix® and Fluophase™ columns commerciallyavailable from Keystone Scientific, Inc. (Bellefonte, Pa.), andFluoroSep™-RP-Octyl commercially available from ES Industries (Berlin,N.J.). Other fluorous separation techniques suitable for the presentinvention include liquid-liquid based separation methods such asliquid-liquid extraction or countercurrent distribution with a fluoroussolvent and an organic solvent. Several fluorous reaction and separationtechniques are disclosed, for example, in U.S. Pat. Nos. 6,156,896;5,859,247 and 5,777,121, the disclosures of which are incorporatedherein by reference in their entirety. In addition, several fluorousreaction and separation techniques are disclosed in U.S. patentapplication Ser. No. 09/506,779; Ser. No. 09/565,087; Ser. No.09/583,247; Ser. No. 09/932,903; Ser. No. 09/977,944 and Ser. No.10/094,345, the disclosures of which are incorporated by referenceherein in their entirety. As used herein, the term “catch and release”refers, generally, to the process of tagging (catching) a compound witha tag and then later detagging (releasing) the tagged compound.

[0057] As used herein, the terms “alkyl”, “aryl” and other groups refer,generally, to both unsubstituted and substituted groups, unlessspecified to the contrary. Unless otherwise specified, alkyl groups arehydrocarbon groups, and are typically C₁-C₁₅ (that is, having 1 to 15carbon atoms) alkyl groups, and may be C₁-C₁₀ alkyl groups, and can bebranched or unbranched, acyclic or cyclic. The above definition of analkyl group and other definitions apply also when the group is asubstituent on another group. The term “aryl” refers to phenyl (Ph) ornaphthyl, substituted or unsubstituted.

[0058] The groups set forth above, can be substituted with a widevariety of substituents. For example, alkyl groups may be substitutedwith a group or groups including, but not limited to, halide(s). As usedherein, the terms “halide” or “halo” refer to fluoro, chloro, bromo andiodo. Aryl groups may be substituted with a group or groups including,but not limited to, halide(s), alkyl group(s), cyano group(s), and/ornitro group(s) and/or mixtures thereof. Halide substituents, for bothalkyl and aryl groups, are typically F and Cl.

[0059] As used herein, the term “functional group” refers, generally, toan atom or a group of atoms that has similar chemical propertieswhenever it occurs in different compounds and confers a specificreactivity to the molecule in which it is contained. For example,functional groups include, but are not limited to, alcohols, thiols,amines, aldehydes, ketones, sulfonic acids, aryl halides, phenols,hydrazines, amino esters, acid chlorides, sulfonyl chlorides, acidanhydrides, chloroformates, isocyanates, isothiocyanates, imines,halides, boronic acids, hydroxylamines, organometallic reagents,carboxylic acids, esters, amides and other derivatives of carboxylicacids. The term “scaffold”, as used herein, refers, generally, to askeletal framework of carbon atoms, in certain cases interspersed withheteroatoms such as, but not limited to, nitrogen, oxygen, sulfur orphosphorous, which is common to all compounds within a specific class ofreagents. As used herein, the term “protecting group” refers, generally,to a grouping of atoms that can be readily attached to an organicfunctional group, such that the organic functional group is renderedless reactive to subsequent chemical transformations. It is a necessaryaspect of a protecting group that the grouping of atoms can be readilyremoved from the substrate after the subsequent chemical transformationsto reveal the organic functional group.

[0060] As used herein, the term “nucleophilic group” refers generally toan electron rich ion, atom, or group of atoms that can donate a pair ofelectrons to another atomic nucleus to form a covalent bond or forms anionic bond with a positively charged ion. The term “electrophilic group”refers generally to an electron deficient ion, atom or group of atomsthat accepts a pair of electrons from a nucleophile to form a covalentbond or forms an ionic bond with a negatively charged ion.

[0061] As used herein, the term “leaving group” refers generally to anatom or a group of atoms that have the potential to leave a reactingmolecule as a relatively stable, weakly basic molecule or ion, when thereacting molecule is attacked by a nucleophile. Attack by thenucleophile results in the formation of a new carbon-nucleophile bondand cleavage of the carbon-leaving group bond. Examples of leavinggroups include, but are not limited to, halide, —N₃, —CN, —OR, —ONH₂,—ONHR, —ONR₂, —O₂CR, —O₂COR, —O₂CNR₂, —SR, —OC(S)R, —S₂CR, —SC(O)SR,—S₂CSR, —O₂CSR, —OC(S)OR, —S₂COR, RSO₂—, RSO₃—, ROSO₂—, ROSO₃—, RPO₃—,ROPO₃—, an N-imidazolyl group, an N-triazolyl group, an N-benzotriazolylgroup, a benzotriazolyloxy group, an imidazolyloxy group, anN-imidazolinone group, an N-imidazolone group, an N-imidazolinethionegroup, an N-succinimidyl group, an N-phthalimidyl group, anN-succinimidyloxy group, an N-phthalimidyloxy group, —ON═C(CN)R, and a2-pyridyloxy group, where R is an alkyl, aryl, benzyl or perfluoroalkylsubstitutent.

[0062] As used herein, the term “electron withdrawing group” refersgenerally to an electron deficient atom or group of atoms that, whenattached to an aromatic ring, withdraws electron density from thearomatic electron system. Examples of electron withdrawing groupsinclude, but are not limited to, halides, nitro group(s), cyanogroup(s), carbonyl group(s), and sulfonate group(s). Electronwithdrawing groups may typically be a chloro, fluoro, nitro and cyanogroup.

[0063] The present invention includes methods and compositions forincreasing the fluorous nature of an organic compound by reacting itwith at least one fluorous compound to produce a fluorous tagged organiccompound. The increased fluorous nature of the fluorous tagged organiccompound can then be utilized to separate the fluorous tagged organiccompound from untagged reagents, reactants, catalysts and/or productsderived therefrom. The resultant fluorous tagged organic compound may besubjected to subsequent chemical transformations, wherein the fluorousnature of the tagged products is utilized to increase the ease ofseparation of the fluorous tagged organic compound from untaggedreagents, reactants, catalysts and/or products derived therefrom, aftereach chemical transformation. The chemical transformations produce asecond fluorous tagged organic compound wherein the fluorous nature ofthe second fluorous tagged organic compound can then be reduced byremoving the fluorous group therefrom, thereby producing a secondorganic compound whose uses include, but are not limited to, aspharmaceutical compounds or intermediates, and combinatorial librarycomponents.

[0064] For the further development of fluorous chemistry into apractical strategy in, for example, combinatorial and parallelsynthesis, a variety of fluorous tags must be made available. Thepresent invention provides fluorous tags and scavengers that can beprepared in large quantity, can be installed and removed, if necessary,from a substrate using mild reaction conditions, and can be recyclableafter cleavage. In addition, the fluorous tags of the present inventionare tolerant, as a group, to a wide range of reaction conditions, suchthat an appropriate tag can be chosen which is amenable to substantiallyany given sequence of reactions.

[0065] The resulting fluorous “tagged” compound can be used in a widevariety of fluorous reaction and can be easily separated from untaggedreagents, reactants, catalysts and/or products derived therefrom, usingseparation techniques that may include standard or fluorous separationtechniques known to those of ordinary skill in the art. The taggingcompounds of the present invention are particularly suitable for taggingor scavenging of compounds bearing a variety of functional groups.

[0066] In a first embodiment, the present invention provides compoundsfor increasing the fluorous nature of an organic compound having thegeneral structure of:

X—CR¹R²—C₆H_(5-m)—[W_(p)(CH₂)_(n)R_(f)]_(m)  (I)

[0067] that possesses a fluorous substituted benzyl scaffold in which Xcan be a leaving group, a nucleophilic group or an electrophilic group,wherein the benzylic carbon can be substituted by a variety of potentialsubstituents, R¹ and R². The fluorous compounds are useful for thetagging a variety of functional groups in either tagging or scavengingprocesses. Functionality reactive with fluorous compound (I) include,but are not limited to, alcohols, amines, thiols carboxylic acids,sufonic acids, aryl halides, acid halides, acid anhydrides,chloroformates, aldehydes, isocyanates, isothiocyanates,sulfonylchlorides, acidic phenols, activated esters, imines, benzylhalides, allyl halides, metals (such as Ni, Pd, etc.), oxidation agents,carbocations, excess acid, hydrazines and/or mixtures thereof.

[0068] The phenyl ring of fluorous compound (I) may have up to 5substitutions, more typically 1 to 3 substitutions, wherein thesubstituent(s) on the phenyl ring have an increased fluorous nature. Thesubstituent(s) consist of a fluorous group, R_(f), as defined abovewhich may be attached to the phenyl ring by an methylene spacerconsisting of n carbon atoms where n is an integer from 0 to 5 and apossible substituent W (when p is 1) situated between the phenyl ringand the methylene spacer. W may be either carbon or a heteroatom, havingthe structure O, S, NR³, CR⁴R⁵, or SiR⁶R⁷, wherein R³, R⁴, and R⁵ areindependently, the same or different, either hydrogen, linear alkyl,branched alkyl, aryl, benzyl or —(CH₂)_(n′″)R_(f) and R⁶ and R⁷ areindependently, the same or different, either linear alkyl, branchedalkyl, aryl, benzyl and —(CH₂)_(n′″)R_(f), wherein n′″ in an integerfrom 0 to 5.

[0069] Where component X in fluorous compound (I) is a leaving group,then at least one fluorous compound (I) reacts with at least onenucleophilic organic compound via an organic reaction mechanismpotentially of the S_(N)1 or S_(N)2 type. The nucleophilic atom of theorganic compound replaces the leaving group X, forming at least onecovalent bond between the organic compound and—CR¹R²—C₆H_(5-m)—[W_(p)(CH₂)_(n)R_(f)]_(m).

[0070] Component X in fluorous compound (I) may be a leaving group thatis a halide, methane sulfonate, p-toluenesulfonate,trifluoromethanesulfonate or perfluoroalkylsulfonate.

[0071] When X is a leaving group, the groups R¹ and R² in fluorouscompound (I) may be both hydrogen (except for when both X is bromine andW is silicon) or one or both of R¹ and R² can be alkyl. The resultantcompounds are fluorous benzyl-tagging reagents. Like traditional benzylreagents, the present compound can react with alcohols, thiols, amines,carboxylic acids, sulfonic acids and other nucleophiles. For a generaldiscussion of the use of non-fluorous benzyl reagents, see Greene, T.W.; Wuts, P. G. M. “Protective Groups in Organic Synthesis,” 3rd ed.,Wiley-Interscience, New York, 1999 and Kocienski, P. “ProtectingGroups,” Thieme, Stuttgart, 1994. However, the fluorous benzyl taggingreagents of the present aspect have advantages over other traditionalnon-fluorous benzyl reagents, in that they facilitate separation of thetagged products from each other and from non-tagged reaction components.

[0072] Both the groups R¹ and R² in fluorous compound (I), where X is aleaving group, may be phenyl or substituted phenyl. The substituent onthe phenyl group may be up to 5 groups, more typically 1 to 3 groups,each independently, the same or different, having the structure, OR⁸,SR⁹, NR¹⁰R¹¹, CR¹²R¹³R¹⁴, SiR¹⁵R¹⁶R¹⁷, [W_(p′)(CH₂)_(n′)R_(f)]_(m′) or[W_(p″)(CH₂)_(n″)R_(f)]_(m″), where R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, and R¹⁴are independently, the same or different, either hydrogen, linear alkyl,branched alkyl, aryl, benzyl or —(CH₂)_(n′″)R_(f), and R¹⁵, R¹⁶, and R¹⁷are independently, the same or different, either linear alkyl, branchedalkyl, aryl, benzyl and —(CH₂)_(n′″)R_(f), wherein n′″ in an integerfrom 0 to 5. When the substituent is [W_(p′)(CH₂)_(n′)R_(f)]_(m′) or[W_(p″)(CH₂)_(n″)R_(f)]_(m″), the substituent(s) consist of a fluorousgroup, R_(f), as defined above which may be attached to the phenyl ringby an methylene spacer consisting of n carbon atoms where n′ and n″ areeach integers from 0 to 5 and a possible substituent W (when p′ or p″is 1) situated between the phenyl ring and the methylene spacer. W maybe either carbon or a heteroatom, having the structure O, S, NR³, CR⁴R⁵,or SiR⁶R⁷, wherein R³, R⁴, and R⁵ are independently, the same ordifferent, either hydrogen, linear alkyl, branched alkyl, aryl, benzylor —(CH₂)_(n′″)R_(f) or R⁶ and R⁷ are independently, the same ordifferent, either linear alkyl, branched alkyl, aryl, benzyl and—(CH₂)_(n′″)R_(f), wherein n′″ in an integer from 0 to 5. The resultantcompounds are fluorous trityl-tagging reagents. Like traditional trityltagging reagents, the present compound can react with alcohols, thiols,amines, carboxylic acids, sulfonic acids and other nucleophiles, and/ormixtures thereof. For a general discussion of the use of non-fluoroustrityl reagents, see Greene, T. W.; Wuts, P. G. M. “Protective Groups inOrganic Synthesis,” 3rd ed., Wiley-Interscience, New York, 1999 andKocienski, P. “Protecting Groups,” Thieme, Stuttgart, 1994. However, thefluorous trityl-tagging reagents of the present aspect have advantagesover other traditional non-fluorous trityl reagents, in that theyfacilitate separation of the tagged products from each other and fromnon-tagged reaction components.

[0073] Fluorous benzylating reagents such as fluorous compound (I),where X is a leaving group as defined above, may be prepared by one ofvarious schemes that employ a combination of organic techniques. Forexample, one possible scheme for the preparation of fluorous benzylhalide is disclosed in Scheme 1.

[0074] A scheme for the preparation of a fluorous trityl reagent isdisclosed in Scheme 2.

[0075] Where component X in fluorous compound (I) is a nucleophilicgroup, at least one fluorous compound (I) reacts with at least oneelectrophilic organic compound via an organic reaction mechanism. Thechemical reaction results in a chemical bond, either covalent or ionic,between the organic compound and the compound of the present aspect ofthe invention. Component X in fluorous compound (I) may be anucleophilic group that is —OH, —NH, —NHR¹⁹, —NR¹⁹R²⁰, —NHC(═NH)NH₂,—SH, —SR¹⁹, —NH(CH₂)_(n″″)NH₂, or —NH(CH₂)_(n″″)N((CH₂)_(n″″)NH₂)₂,wherein n″″ is an integer from 1 to 5, and R¹⁹ and R²⁰ areindependently, the same or different, either a linear alkyl, a branchedalkyl, an aryl or a benzyl group.

[0076] Where nucleophilic component X in fluorous compound (I) is —SH,the groups R¹ and R² can both be hydrogen, both alkyl or both benzylgroups. In an alternative structure, one of R¹ and R² can be hydrogenand the other alkyl or benzyl. The resultant compounds are fluorousbenzyl thiol reagents. Fluorous benzyl thiol reagents can react withnumerous electrophilic components, for example, but not limited to, arylhalides, bromomethylcarbonyl compounds, benzyl halides, allyl halidesand other electrophiles and/or mixtures thereof. They can also be usedin the scavenging of metals including Ni, Pd, and the like.

[0077] Where nucleophilic component X in fluorous compound (I) is —SR¹⁹,the groups R¹ and R² can both be hydrogen, both alkyl or both benzylgroups. In an alternative structure, one of R¹ and R² can be hydrogenand the other alkyl or benzyl. R¹⁹ can be alkyl, aryl or benzyl. Theresultant compounds are fluorous benzyl sulfide reagents. Fluorousbenzyl sulfide reagents have potential application including, but notlimited to, scavenging oxidation agents and carbocations, for example,carbocations produced in peptide deprotection reactions.

[0078] Where nucleophilic component X in fluorous compound (I) is asubstituted nitrogen having the structure: —NH₂, —NHR²¹, —NR²¹R²² or—NR²¹R²²R²³⁺Y⁻, the groups R¹ and R² can both be hydrogen, both alkyl orboth benzyl groups. In an alternative structure, one of R¹ and R² can behydrogen and the other alkyl or benzyl. R²¹, R²² and R²³ areindependently, the same or different, a linear alkyl, a branched alkylor a benzyl group and Y⁻ is a counter anion such as, but not limited to,Cl⁻, Br⁻, I⁻ and CO₃ ²⁻. The resultant compounds are fluorous primarybenzylamines, fluorous secondary benzylamines, fluorous tertiarybenzylamines and fluorous quaternary benzylammonium salts. Fluorousprimary benzylamines, fluorous secondary benzylamines, and fluoroustertiary benzylamines have potential applications including, but notlimited to, scavenging excess acid from a reaction or reacting withcarboxylic acids, sulfonic acids, acid halides, acid anhydrides,chloroformates, aldehydes, isocyanates, isothiocyanatessulfonylchlorides and other electrophiles and/or mixtures thereof.Fluorous tertiary benzylamines also have the potential application as abase, for example, in combination with other fluorous reagents such asF-Trisamine, F-isocyanate, or F-thiol scavengers (the prefix “F-”, asused herein, is an abbreviation of “fluorous”), or in the mesylationreaction of alcohols. Fluorous quaternary benzylammonium salts usesinclude, but are not limited to, scavenging acids, acidic phenols,activated ester electrophiles and/or mixtures thereof, and having thepotential utility to quench reactions and neutralize ammonium salts.

[0079] Nucleophilic component X in fluorous compound (I) may be ahydroxyl group, wherein the groups R¹ is hydrogen and R² has thestructure C₆H_(5-q)(W′)_(q). The integer value of q is from 0 to 5, moretypically from 0 to 3. W′ can be the grouping of atoms OR⁸, SR⁹,NR¹⁰R¹¹, CR¹²R¹³R⁴¹, or SiR¹⁵R¹⁶R¹⁷, wherein R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³,and R¹⁴ are independently, the same or different, either hydrogen,linear alkyl, branched alkyl, aryl, benzyl or —(CH₂)_(n′″)R_(f) or R¹⁵,R¹⁶, and R¹⁷ are independently, the same or different, either linearalkyl, branched alkyl, aryl, benzyl or —(CH₂)_(n′″)R_(f), wherein n′″ inan integer from 0 to 5. The resultant compounds are fluorous bisbenzylalcohols. Fluorous bisbenzyl alcohols uses include, but are not limitedto, reacting with alcohols and carboxylic acids and/or mixtures thereof,thereby tagging the compound and simplifying separation/purification.

[0080] Nucleophilic component X in fluorous compound (I) may be an aminogroup, wherein R¹ is hydrogen and R² has the structureC₆H_(5-q)(W′)_(q). The integer value of q is from 0 to 5, more typicallyfrom 0 to 3. W′ can be the grouping of atoms OR⁸, SR⁹, NR¹⁰R¹¹,CR¹²R¹³R¹⁴, or SiR¹⁵R¹⁶R¹⁷, wherein R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, and R¹⁴are independently, the same or different, either hydrogen, linear alkyl,branched alkyl, aryl, benzyl or —(CH₂)_(n′″)R_(f) and R¹⁵, R¹⁶, and R¹⁷are independently, the same or different, either linear alkyl, branchedalkyl, aryl, benzyl or —(CH₂)_(n′″)R_(f), wherein n′″ in an integer from0 to 5. The resultant compounds are fluorous bisbenzyl amines. Fluorousbisbenzyl amines uses include, but are not limited to, their reactionwith carboxylic acids and sulfonic acids and/or mixtures thereof,thereby tagging the compound and simplifying separation/purification.

[0081] Where nucleophilic component X in fluorous compound (I) is—NH(CH₂)_(n″″)NH₂, the groups R¹ and R² can both be hydrogen, both alkylor both benzyl groups. In an alternative structure, one of R¹ and R² canbe hydrogen and the other alkyl or benzyl. The integer value for n″″ is1 to 5. The resultant compounds are fluorous benzyl diamines. Fluorousbenzyl diamines have uses including, but not limited to, quenchingactivated carbonyl acids, sulfonyl halides, isocyanates, isothiocyanatesand other electrophiles or mixtures thereof, and also scavenging excessacid. Subsequent to reaction, the tagged compound can be easily removedfrom the reaction mixture.

[0082] Where nucleophilic component X in fluorous compound (I) is—NH(CH₂)_(n″″)N((CH₂)_(n″″)NH₂)₂, the groups R¹ and R² can both behydrogen, both alkyl or both benzyl groups. In an alternative structure,one of R¹ and R² can be hydrogen and the other alkyl or benzyl. Theinteger value for n″″ is 1 to 5. The resultant compounds are fluorousbenzyl trisamines. Fluorous benzyl trisamines uses include, but are notlimited to, their reaction with carboxylic acids, acid chlorides,sulfonyl halides, isocyanates, isothiocyanates, imines and otherelectrophiles of mixtures thereof, and scavenging excess acid.Subsequent to reaction, the tagged compound can be easily removed fromthe reaction mixture.

[0083] Where nucleophilic component X in fluorous compound (I) is—NHC(═N)NH₂, the groups R¹ and R² can both be hydrogen, both alkyl orboth benzyl groups. In an alternative structure, one of R¹ and R² can behydrogen and the other alkyl or benzyl. The resultant compounds arefluorous benzyl guanidines. Fluorous benzyl guanidines have thepotential use including, but not limited to, acting as strong organicbases.

[0084] Fluorous reagents such as fluorous compound (I), where X is anucleophilic group as defined above, may be prepared by one of variousschemes that employ a combination of organic techniques. For example,one possible scheme for the preparation of fluorous benzyl thiolreagents is disclosed in Scheme 3.

[0085] One possible scheme for the preparation of a fluorous benzylsulfide reagent is disclosed in Scheme 4.

[0086] Two possible routes for preparing of fluorous benzylaminereagents are shown in Scheme 5.

[0087] Fluorous quaternary benzylammonium salts can be prepared as setforth in Scheme 6.

[0088] Fluorous bisbenzyl alcohols may be prepared by addition of asubstituted phenyl Grignard reagent to a fluorous benzaldehyde as shownin Scheme 7.

[0089] Fluorous bisbenzyl amines may be prepared from fluorous bisbenzylalcohols through the chemical transformations shown in Scheme 8.

[0090] A route to a fluorous benzyl diamine is shown in Scheme 9 and ananalogous route to a fluorous benzyl trisamine is depicted in Scheme 10.

[0091] An approach to a fluorous benzyl guanidine is depicted in Scheme11.

[0092] The fluorous nucleophilic benzyl tags and scavengers discussedabove may be synthesized using one or more of the synthetic approachesset forth in Schemes 1-11.

[0093] Where component X in fluorous compound (I) is an electrophilicgroup, at least one fluorous compound (I) reacts with at least onenucleophilic organic compound via an organic reaction mechanism. Thechemical reaction results in a chemical bond, either covalent or ionic,between the organic compound and the compound of the present aspect ofthe invention.

[0094] Where electrophilic component X in fluorous compound (I) is theelectrophilic group comprising either an isocyanate group or anisothiocyanate group, the groups R¹ and R² can both be hydrogen, bothalkyl or both benzyl groups. In an alternative structure, one of R¹ andR² can be hydrogen and the other alkyl or benzyl. The resultantcompounds are fluorous benzyl isocyanates and isothiocyanates. Fluorousbenzyl isocyanates and isothiocyanates have uses including, but notlimited to, their reaction with amines, hydrazines and othernucleophiles or mixtures thereof, for the purpose of tagging/scavengingthose compounds for separation from the reaction mixture.

[0095] Fluorous reagents such as fluorous compound (I), where X is anelectrophilic group, may be prepared by one of various schemes thatemploy a combination of organic techniques. For example, one possiblescheme for the preparation of fluorous isocyanate and isothiocyanatereagents is disclosed in Scheme 12.

[0096] In an alternative structure to the structures comprising fluorouscompound (I), R_(f) is a fluorous group selected from a perfluorocarbon,a fluorohydrocarbon, a fluorinated ether or a fluorinated amine.

[0097] The present invention also provides a method for increasing thefluorous nature of an organic compound, including reacting the organiccompound with at least one second compound having the general structureof fluorous compound (I) as described above, to create a first fluoroustagged organic compound. The organic compound will have at least onefunctional group reactive with group X on the fluorous second compound(I) forming at least one chemical bond between the organic compound andthe fluorous second compound (I), resulting in the first fluorous taggedorganic compound. The fluorous nature of the first fluorous taggedorganic compound is increased relative to the organic compound to enableseparation of the first fluorous tagged organic compound from at leastone other compound by using separation techniques that may includestandard or fluorous separation techniques known to those of ordinaryskill in the art.

[0098] In the method for increasing the fluorous nature of an organiccompound by reacting it with at least one second compound having thestructure of fluorous compound (I), described above, wherein X is aleaving group, the leaving group X in fluorous compound (I) may be thoseleaving groups defined above. Where fluorous compound (I) is a benzyltagging reagent, as described above, the resultant fluorousbenzyl-tagging reagents have uses including, but not limited to, taggingalcohols, thiols, amines, carboxylic acids, sulfonic acids and othernucleophilic organic compounds and/or mixtures thereof, wherein thefluorous benzyl tagged compounds can be separated from other reactioncomponents through separation techniques that may include standard orfluorous separation techniques known to those of ordinary skill in theart. Where fluorous compound (I) is a trityl tagging reagent, asdescribed above, the resultant fluorous trityl-tagging reagents haveuses including, but not limited to, the tagging of alcohols, thiols,amines, carboxylic acids, sulfonic acids and other nucleophiles and/ormixtures thereof, wherein the fluorous trityl tagged compounds can beseparated from other reaction components through separation techniquesthat may include standard or fluorous separation techniques known tothose of ordinary skill in the art.

[0099] In the method for increasing the fluorous nature of an organiccompound by reacting it with at least one second compound having thestructure of fluorous compound (I), described above, wherein X is anucleophilic group, the nucleophilic group X in fluorous compound (I)may be those nucleophilic groups defined above, and at least onefluorous compound (I) reacts with at least one electrophilic organiccompound via an organic reaction mechanism. The chemical reactionresults in a chemical bond, either covalent or ionic, between theorganic compound and the compound of the present aspect of theinvention. In the above method of the present invention, the fluoroustagged or scavenged organic compounds can then be separated from thereaction mixture by a separation technique that may include a standardor fluorous separation technique known to those skilled in the art. Thetagged compounds may then be subjected to subsequent chemicaltransformations.

[0100] In the method for increasing the fluorous nature of an organiccompound by reacting it with at least one second compound having thestructure (I) where component X in fluorous compound (I) may be anelectrophilic group as defined above, at least one fluorous compound (I)reacts with at least one nucleophilic organic compound via an organicreaction mechanism. The chemical reaction results in a chemical bond,either covalent or ionic, between the organic compound and the compoundof the present aspect of the invention. Where electrophilic component Xin fluorous compound (I) is the electrophilic group comprising either anisocyanate group or an isothiocyanate group, the resultant compounds arefluorous benzyl isocyanates and isothiocyanates. Fluorous benzylisocyanates and isothiocyanates have uses including, but not limited to,reacting with amines, hydrazines and other nucleophilic reagents and/ormixtures thereof, wherein the fluorous tagged compounds can be separatedfrom other reaction components through separation techniques that mayinclude standard or fluorous separation techniques known to those ofordinary skill in the art.

[0101] In addition, the method of the present invention may furtherinclude reducing the fluorous content of a second fluorous-taggedorganic compound that is tagged with fluorous compound (I). In thisaspect of the invention, the first fluorous-tagged organic compound, inwhich the tag is from fluorous compound (I), is subjected to at leastone chemical reaction and potentially at least one purification process.The chemical reaction(s) produces the second fluorous-tagged organiccompound, in which the tag is from fluorous compound (I), which isisolated and subjected to the fluorous content reducing step. Theresultant molecules may have uses that include, but are not limited to,pharmaceutical compounds or intermediates, and combinatorial librarycomponents.

[0102] The fluorous nature of the second fluorous-tagged organiccompound may be reduced by removing at least one grouping of atomshaving the possible structure:—CR¹R²—C₆H_(5-m)—[W_(p)(CH₂)_(n)R_(f)]_(m),—C₆H_(5-m)—[W_(p)(CH₂)_(n)R_(f)]_(m), —[W_(p)(CH₂)_(n)R_(f)]_(m),(CH₂)_(n)R_(f), or R_(f) from the second fluorous tagged organiccompound.

[0103] In another embodiment, the present invention provides compoundsfor increasing the fluorous nature of an organic compound having thegeneral structure of:

XCO₂CH₂R_(d)  (II)

[0104] wherein X is a leaving group and R_(d) has the structure selectedfrom:

[0105] a) —CH═CH—(CH₂)_(n)R_(f), b) or c)—C₆H_(5-m″)[W_(p)(CH₂)_(n)R_(f)]_(m″). R_(f) and R_(f′) are eachfluorous groups. The integer value for m is from 1 to 4, m′ is aninteger from 0 to 4, and m″ is an integer from 1 to 5, more typicallyfrom 1 to 3. The integer values for n and n′ are each from 0 to 5 and pand p′ each has a value of either 0 or 1. W and W′ are atoms orgroupings of atoms each having the possible structure of O, S, NR²⁵,CR²⁶R²⁷, or SiR²⁸R²⁹. The substituents R²⁵, R²⁶ and R²⁷ areindependently, the same or different, either hydrogen, linear alkyl,branched alkyl, aryl, benzyl or CH₂)_(n)R_(f), and the substituents R²⁸and R²⁹ are independently, the same or different, either linear alkyl,branched alkyl, aryl, benzyl or —(CH₂)_(n)R_(f).

[0106] Component X in fluorous compound (II) may be various leavinggroups suitable for use in the present invention and known to thoseskilled in the art. X may be a leaving group with a structure consistingof a halide, —N₃, —CN, —OR³⁰, —ONH₂, —ONHR₃, ONR³⁰, —O₂CR³⁰, —O₂COR³⁰,—O₂CNR³⁰ ₂, —SR³⁰, —OC(S)R³⁰, R³⁰CS₂—, —SC(O)SR³⁰, —SCS₂R³⁰, —OC(O)SR³⁰,—OC(S)OR³⁰, —SC(S)OR³⁰, R³⁰SO₂—, R³⁰SO₃—, R³⁰OSO₂—, R³⁰OSO₃—, R³⁰PO₃—,R³⁰OPO₃—, an N-imidazolyl group, an N-triazolyl group, anN-benzotriazolyl group, a benzotriazolyloxy group, an imidazolyloxygroup, an N-imidazolinone group, an N-imidazolone group, anN-imidazolinethione group, an N-succinimidyl group, an N-phthalimidylgroup, an N-succinimidyloxy group, an N-phthalimidyloxy group,—ON═C(CN)R³⁰, or a 2-pyridyloxy group, wherein R³⁰ is one of linearalkyl, branched alkyl, aryl, benzyl, or —(CH₂)_(n″)R_(f), wherein n″ inan integer from 0 to 5.

[0107] For the purpose of this embodiment, R_(f) and R_(f)′ may beindependently, the same or different, selected from a perfluorocarbon, afluorohydrocarbon, a fluorinated ether or a fluorinated amine.

[0108] Where R_(d) of fluorous compound (II) has the structure—CH═CH—(CH₂)_(n)R_(f) (i.e. group (a)), the resultant compounds arefluorous allyloxycarbonyl reagents (F-Alloc). Where R_(d) in fluorouscompound (II) has the structure:

[0109] (i.e. group (b)), the resultant compounds are fluorous9-fluorenylmethoxycarbonyl reagents (F-Fmoc). Where R_(d) in fluorouscompound (II) has the structure —C₆H_(5-m″)[W_(p)(CH₂)_(n)R_(f)]_(m″)(i.e. group (c)), the resultant compounds are fluorous carboxybenzylreagents (F-Cbz). Like traditional allyloxycarbonyl,9-fluorenylmethoxycarbonyl, and carboxybenzyl reagents, the presentcompounds can react with amines. For a general discussion of the use ofnon-fluorous allyloxycarbonyl, 9-fluorenylmethoxycarbonyl, andcarboxybenzyl reagents, see Greene, T. W.; Wuts, P. G. M. “ProtectiveGroups in Organic Synthesis,” 3rd ed., Wiley-Interscience, New York,1999 and Kocienski, P. “Protecting Groups,” Thieme, Stuttgart, 1994.However, the fluorous allyloxycarbonyl, fluorous9-fluorenylmethoxycarbonyl, and fluorous carboxybenzyl tagging reagentsof the present invention have advantages over other traditionalnon-fluorous allyloxycarbonyl, 9-fluorenylmethoxycarbonyl, andcarboxybenzyl reagents, respectively, in that the fluorous taggingreagents of the present invention tag the organic compound andfacilitate separation of the tagged products from each other and fromnon-tagged reaction components.

[0110] Fluorous reagents such as fluorous compound (II), where R_(d) mayhave the structures as described, may be prepared by one of variousschemes that employ a combination of organic techniques. For example,one possible scheme for the preparation of fluorous allyloxycarbonylreagents is disclosed in Scheme 13.

[0111] A synthetic approach to fluorous fluorenylmethoxycarbonyl(F-Fmoc) reagents is depicted in Scheme 14.

[0112] Fluorous carboxybenzyl reagents may be prepared using theapproach as depicted in Scheme 15.

[0113] The present invention also provides a method for increasing thefluorous nature of an organic compound that includes reacting theorganic compound with at least one second compound having the generalstructure of fluorous compound (II), described above. The organiccompound will have at least one functional group reactive with leavinggroup X on the second compound forming at least one chemical bondbetween the organic compound and the second compound resulting in thefirst fluorous tagged organic compound. The fluorous nature of the firstfluorous tagged organic compound is increased relative to the organiccompound to enable separation of the first fluorous tagged organiccompound from at least one other compound by using separation techniquesthat may include standard or fluorous separation techniques known tothose of ordinary skill in the art.

[0114] In the method for increasing the fluorous nature of an organiccompound by reacting it with at least one second compound having thestructure (II), described above, wherein component X is a leaving group,the leaving group X in fluorous compound (II) may be those leavinggroups defined above. Where fluorous compound (II) is F-Alloc, F-Fmoc orF-Cbz reagent described above, the resultant F-Alloc, F-Fmoc, or F-Cbzreagents, respectively, have uses that include, but are not limited to,reacting with amines such that the fluorous tagged amines may be readilyseparated from other fluorous or non-fluorous reaction components.

[0115] In addition, the method of the present invention may furtherinclude reducing the fluorous content of a second fluorous-taggedorganic compound that is tagged with fluorous compound (II). In thisaspect of the invention, the first fluorous-tagged organic compound, inwhich the tag is from fluorous compound (II), is subjected to at leastone chemical reaction and potentially at least one purification process.The chemical reaction(s) produces the second fluorous-tagged organiccompound, in which the tag is from fluorous compound (II), which isisolated and subjected to the fluorous content reducing step. Theresultant molecules may have uses that include, but are not limited to,pharmaceutical compounds or intermediates, and combinatorial librarycomponents.

[0116] The fluorous nature of the second fluorous-tagged organiccompound may be reduced by removing at least one grouping of atomshaving the possible structure: —CO₂CH₂R_(d), —OCH₂R_(d), R_(d), andR_(f) from the second fluorous tagged organic compound.

[0117] In yet another embodiment, the present invention providescompounds for increasing the fluorous nature of an organic compoundhaving the general structure of:

R³¹R³²N(CH₂)_(n)R_(f)  (III)

[0118] wherein n is an integer from 0 to 5, R_(f) is a fluorous group,and R³¹R³² is selected from: a) —(CH₂)_(m)W(CH₂)_(m′)—, wherein m and m′are each integers between 2 and 4, W is one of CH₂, O, S, NH, and NR³³,wherein R³³ is one of a linear alkyl, a branched alkyl and a benzylgroup,

[0119] wherein m″ and m′″ are each integers from 0 to 3,

[0120] wherein W′ is a grouping of atoms selected from the groupconsisting of O, S, NR³⁴, CR³⁵R³⁶, SiR³⁷R³⁸, p has a value of 0 or 1, n′is an integer from 0 to 5, m″″ is an integer from 0 to 4, more typicallyfrom 0 to 2, R³⁴, R³⁵, and R³⁶ are independently, the same or different,one of hydrogen, linear alkyl, branched alkyl, aryl, benzyl and—(CH₂)_(n)R_(f), and R³⁷ and R³⁸ are independently, the same ordifferent, one of linear alkyl, branched alkyl, aryl, benzyl and—(CH₂)_(n)R_(f),

[0121] d) alkyl and pyridyl,

[0122] e) hydrogen and —(CH₂)_(n″)NH₂, wherein n″ is an integer from 1to 5,

[0123] f) hydrogen and —(CH₂)_(n″)N[(CH₂)_(n″)NH₂]₂, or

[0124] g) —(CH₂)_(n′″)OH, and —(CH₂)_(n″″)OH, wherein n′″ and n″″ areeach integers between 1 and 5.

[0125] For the purpose of this embodiment, R_(f) may be aperfluorocarbon, a fluorohydrocarbon, a fluorinated ether or afluorinated amine.

[0126] In fluorous compound (III), the groups R⁻R³², taken together, maybe —(CH₂)_(m)W(CH₂)_(m′)—, forming a cyclic amine, where W, m and m′ areas defined above. The resultant compounds are fluorous cyclic aminesthat have various applications including, but not limited to, acting asa tertiary amine to catalyze reactions, as a catalyst in thefunctionalization of secondary amines with acid chlorides and as ascavenger to remove excess acid.

[0127] For fluorous compound (III), the groups, R³¹R³², taken together,may have the structure:

[0128] forming a bicyclic amine, wherein m″ and m′″ are each integersfrom 0 to 3. The resultant compounds are fluorous bicyclic amines thathave potential utility as, but not limited to, a fluorous basic catalystfor regioselective acylation, as both a base for the deprotonation ofphenols and as a scavenger of excess phenol in the synthesis of arylethers, in the addition of dialkyl phosphates to a variety of carbonylcompounds, as a catalyst in the nitroaldol reaction and as a scavengerof activated ester electrophiles.

[0129] For fluorous compound (III), the groups R³¹R³², taken together,may have the structure:

[0130] forming a cyclic isatoic anhydride, wherein W′, p, n′, and m″″are as defined above. The resultant compounds are fluorous isatoicanhydrides that have potential applications including, but not limitedto, the scavenging of primary and secondary amines, and/or mixturesthereof, wherein the scavenged amines may be removed from the reactionmixture through separation techniques that may include standard orfluorous separation techniques known to those of ordinary skill in theart.

[0131] In fluorous compound (III), the nitrogen may be substituted whereR³¹ is one of linear alkyl and branched alkyl, and R³² is a pyridylring, wherein the nitrogen may be attached to the pyridyl ring at the 2,3, or 4 position. The resultant compounds are fluorous aminopyridines.Uses of fluorous aminopyridines include, but are not limited to, as anequivalent to dimethylaminopyridine for the catalysis of acylation oresterification reactions, and as a reagent for the “catch and release”of acid chlorides and sulfonyl chlorides in the synthesis of acyl andsulfonyl derivatives, including esters, amides, sulfonamides and/ormixtures thereof.

[0132] The nitrogen of fluorous compound (III) may also be substitutedwhere R³¹ is hydrogen and R³² is CH₂)_(n″)NH₂, wherein n″ is an integerfrom 1 to 5. The resultant compounds are fluorous alkyldiamines.Fluorous alkyldiamines have uses including, but not limited to,quenching activated carbonyl acids, sulfonyl halides, isocyanates,isothiocyanates and other electrophiles and/or mixtures thereof, andalso the scavenging of excess acid.

[0133] The nitrogen of fluorous compound (III) may also be substitutedwhere R³¹ is hydrogen and R³² is —(CH₂)_(n″)N[(CH₂)_(n″)NH₂]₂, whereinn″ is an integer from 1 to 5. The resultant compounds are fluorousalkyl(trisaminoalkyl) amines. Fluorous alkyl(trisaminoalkyl) amines haveuses including, but not limited to, quenching activated carbonyl acids,sulfonyl halides, isocyanates, isothiocyanates and other electrophilesand/or mixtures thereof. The compounds can also be useful in thescavenging of excess acid.

[0134] The nitrogen of fluorous compound (III) may also be substitutedwherein R³¹ is —(CH₂)_(n′″)OH, and R³² is —(CH₂)_(n″″)OH, wherein n′″and n″″ are each integers between 1 and 5. The resultant compounds arefluorous N,N-dihydroxyalkylamines. Fluorous N,N-dihydroxyalkylamineshave uses including, but not limited to, quenching of boronic acids. Thequenched boronic acids may then be readily removed from the reactionmixture through separation techniques that may include standard orfluorous separation techniques known to those of ordinary skill in theart.

[0135] Fluorous reagents such as (III), where the groups R³¹R³² have thestructures as described, may be prepared by one of various schemes thatemploy a combination of organic techniques. For example, one possiblescheme for the preparation of fluorous cyclic amine reagents isdisclosed in Scheme 16.

[0136] An approach to fluorous reagent (III), wherein compound (III) isa bicyclic amine, is depicted in Scheme 17.

[0137] Where fluorous compound (III) is a fluorous isatoic anhydride,the present embodiment may be prepared as shown in Scheme 18.

[0138] Fluorous aminopyridine reagents may be prepared as shown inScheme 19.

[0139] Where fluorous compound (III) is a fluorous alkyl diamine (Scheme20) or a fluorous alkyl(trisaminoalkyl) amines (Scheme 21), the presentembodiment may be prepared as shown below.

[0140] Fluorous N,N-dihydroxyalkylamines may be prepared as shown inScheme 22.

[0141] The present invention also provides a method for increasing thefluorous nature of an organic compound, including the step of reactingthe organic compound with at least one second compound having thestructure of fluorous compound (III), wherein the groups R³¹R³² may beas described above, to create a first fluorous tagged organic compound.The organic compound having at least one functional group reactive withat least one N or —OH group on the second compound (III) forming atleast one chemical bond between the organic compound and the secondcompound (III) resulting in the first fluorous tagged organic compound.The fluorous nature of the first fluorous tagged organic compound isincreased relative to the organic compound to enable separation of thefirst fluorous tagged organic compound from at least one other compoundby using separation techniques that may include standard or fluorousseparation techniques known to those of ordinary skill in the art. Thetagged compounds may then be subjected to subsequent chemicaltransformations.

[0142] In addition, the method of the present invention may furtherinclude reducing the fluorous content of a second fluorous-taggedorganic compound that is tagged with fluorous compound (III). In thisaspect of the invention, the first fluorous-tagged organic compound, inwhich the tag is from fluorous compound (III), is subjected to at leastone chemical reaction and potentially at least one purification process.The chemical reaction(s) produces the second fluorous-tagged organiccompound, in which the tag is from fluorous compound (III), which isisolated and subjected to the fluorous content reducing step. Theresultant molecules may have uses that include, but are not limited to,pharmaceutical compounds or intermediates, and combinatorial librarycomponents.

[0143] The fluorous nature of the second fluorous-tagged organiccompound may be reduced by removing at least one grouping of atomshaving the possible structure: R³¹R³²N(CH₂)_(n)R_(f), —N(CH₂)_(n)R_(f),—(CH₂)_(n)R_(f), or R_(f) from the second fluorous tagged organiccompound.

[0144] In a further embodiment, the present invention provides compoundsfor increasing the fluorous nature of an organic compound having thegeneral structure of:

X—C₆H_(5-m)—[W_(p)(CH₂)_(n)R_(f)]_(m)  (IV)

[0145] wherein R_(f) is a fluorous group, m has an integer value from 1to 5, more typically from 1 to 3, n has an integer value from 0 to 5, pis either 0 or 1 and W is an atom or grouping of atoms having thestructure of O, S, NR³⁹, CR⁴⁰R⁴¹, or SiR⁴²R⁴³. When W is O, then X hasthe structure —SO₂NHNH₂, —CHO when p is 1, —SH, (CH₂)_(n′)SH,—C(═NOH)C₆H₄Y, or —C(═O)CH₂C(═O)R⁴⁴. When W is S, NR³⁹, CR⁴⁰R⁴¹, orSiR⁴²R⁴³, then X has the structure —SO₂NH₂, —SO₂NHNH₂, —CHO when p is 1,—SH, —(CH₂)_(n′)SH, —C(═NR^(B))C₆H₄Y, or —C(═O)CH₂C(═O)R⁴⁴. Z is eitheroxygen or sulfur. Y is either an electron withdrawing group, a hydrogenor an alkyl group and R^(B) is either a hydrogen, an alkyl, an aryl or ahydroxyl group. The integer value of n′ is from 2 to 5. R³⁹, R⁴⁰ and R⁴¹are independently, the same or different, either hydrogen, linear alkyl,branched alkyl, aryl, benzyl or —(CH₂)_(n)R_(f), and R⁴² and R⁴³ areindependently, the same or different, either linear alkyl, branchedalkyl, aryl, benzyl or —(CH₂)_(n)R_(f). R⁴⁴ is linear alkyl, branchedalkyl or benzyl.

[0146] For the purpose of this embodiment, R_(f) may be aperfluorocarbon, a fluorohydrocarbon, a fluorinated ether or afluorinated amine.

[0147] Where component X in fluorous compound (IV) is —SO₂NH₂, thestructure of W may be S, NR³⁹, CR⁴⁰R⁴¹, or SiR⁴²R⁴³. The resultantcompounds are fluorous benzenesulfonamides. Fluorous benzenesulfonamideshave uses including, but not limited to, scavenging acids, acidchlorides, anhydrides, aldehydes, isocyanates, isothiocyanateschloroformates and other electrophiles and/or mixtures thereof. Thescavenged compounds can be separated from the reaction mixture usingseparation techniques that may include standard or fluorous separationtechniques known to those of ordinary skill in the art.

[0148] Where component X in fluorous compound (IV) is —SO₂NHNH₂, theresultant structures are fluorous sulfonylhydrazides. Fluoroussulfonylhydrazides have uses including, but not limited to, scavengingaldehydes and ketones and/or mixtures thereof. The scavenged compoundscan be separated from the reaction mixture using separation techniquesthat may include standard or fluorous separation techniques known tothose of ordinary skill in the art.

[0149] Where component X in fluorous compound (IV) is —CHO, the value ofp is 1. The resultant structures are fluorous benzaldehydes. Fluorousbenzaldehydes have uses including, but not limited to, selectivelyscavenging primary amines, hydrazines, hydroxylamines, 1,2-aminothiols,Grignard reagents, other organometallic reagents and/or mixturesthereof. The scavenged compounds can be separated from the reactionmixture using separation techniques that may include standard orfluorous separation techniques known to those of ordinary skill in theart.

[0150] Where component X in fluorous compound (IV) is —SH or—(CH₂)_(n′)SH, where the integer value of n′ is from 2 to 5, theresultant structures are fluorous benzenethiols or fluorousarylalkylthiols, respectively. Fluorous benzenethiols and fluorousarylalkylthiols have uses including, but not limited to, reacting withnumerous electrophilic components, for example, aryl halides,bromomethylcarbonyl compounds, benzyl halides, allyl halides and otherelectrophiles, and/or mixtures thereof. They can also be used in thescavenging of metals such as Ni, Pd, and the like. The scavenged ortagged compounds can be separated from the reaction mixture usingseparation techniques that may include standard or fluorous separationtechniques known to those of ordinary skill in the art.

[0151] Component X in fluorous compound (IV) may be —C(═NR^(B))C₆H₄Y,where Y is an electron withdrawing group, a hydrogen or an alkyl groupand R^(B) is a hydrogen, an alkyl group, and aryl group or a hydroxylgroup. Where Y is an electron withdrawing group, it may be selected fromnitro, cyano, fluoro, or chloro. The resultant compounds are fluorousbenzylimines (when R^(B) is hydrogen, alkyl or aryl), or benzyloximes(when R^(B) is hydroxyl), which have uses including, but not limited to,tagging of carboxylic acids. The tagged compounds can be separated fromthe reaction mixture using separation techniques that may includestandard or fluorous separation techniques known to those of ordinaryskill in the art.

[0152] Component X in fluorous compound (IV) may also be—C(═O)CH₂C(═O)R⁴⁴, where R⁴⁴ is linear alkyl, branched alkyl or benzyl.The resultant compounds are fluorous aryl-1,3-diketones. Fluorousaryl-1,3-diketones have uses including, but not limited to, scavengingprimary amines in the presence of secondary amines. The scavengedcompounds can be separated from the reaction mixture using separationtechniques that may include standard or fluorous separation techniquesknown to those of ordinary skill in the art.

[0153] Fluorous reagents such as (IV), where component X is as describedabove, may be prepared by one of various schemes that employ acombination of organic techniques. For example, one possible scheme forthe preparation of fluorous benzenesulfonamide reagents is disclosed inScheme 23.

[0154] A possible route for the synthesis of fluorousbenzenesulfonylhydrazide is depicted in Scheme 24.

[0155] Scheme 25 provides a route to fluorous benzaldehydes.

[0156] Fluorous arylalkylthiols may be synthesized using the approachdepicted in Scheme 26.

[0157] One possible approach to fluorous benzyloximes is shown in Scheme27.

[0158] Fluorous aryl-1,3-diketones may be synthesized using an approachas shown in Scheme 28.

[0159] The present invention also provides a method for increasing thefluorous nature of an organic compound, including the step of reactingthe organic compound with at least one second compound having thestructure of fluorous compound (IV), where component X is as describedabove and also including where component X of fluorous compound (IV) maybe the group —COCl, —SO₂Cl, —OH, —NCZ, or —SO₃H, to create a firstfluorous tagged organic compound. The organic compound has at least onefunctional group that reacts with group X on at least one secondfluorous compound (IV) to form at least one chemical bond between theorganic compound and at least one second fluorous compound (IV). Thechemical reaction results in a first fluorous tagged organic compoundwith an increased fluorous nature relative to the fluorous nature of theorganic compound. The increased fluorous nature of the first fluoroustagged organic compound enables separating the first fluorous taggedorganic compound from other compounds by use of separation techniquesthat may include separation techniques that may include standard orfluorous separation techniques known to those of ordinary skill in theart. The tagged compounds may then be subjected to subsequent chemicaltransformations.

[0160] The present invention may also provide a method for increasingthe fluorous nature of an organic compound by reacting it with at leastone second compound (IV), where component X in fluorous compound (IV)may be —COCl. The resultant compounds are fluorous benzoyl chlorides.Fluorous benzoyl chlorides react alcohols, amines, thiols, and othernucleophiles, and/or mixtures thereof, through a nucleophilic acylsubstitution process to produce a fluorous tagged organic compound.

[0161] The present invention may also provide a method for increasingthe fluorous nature of an organic compound by reacting it with at leastone second compound (IV), where component X in fluorous compound (IV)may be —SO₂Cl. The resultant compounds are fluorous benzenesulfonylchlorides that have uses including, but not limited to, tagging andscavenging alcohols, amines, thiols and other nucleophiles, and/ormixtures thereof.

[0162] The present invention may further provide a method for increasingthe fluorous nature of an organic compound by reacting it with at leastone second compound (IV), where component X in fluorous compound (IV)may be —OH. The resultant compounds are fluorous phenols that have usesincluding, but not limited to, tagging carboxylic acids.

[0163] The present invention may also provide a method for increasingthe fluorous nature of an organic compound by reacting it with at leastone second compound (IV), where component X in fluorous compound (IV)may be —NCZ, where Z is either oxygen or sulfur. The resultant compoundsare fluorous phenyl isocyanates or fluorous phenyl isothiocyanates thathave uses including, but not limited to, scavenging amines, hydrazinesand other nucleophiles, and/or mixtures thereof.

[0164] The present invention may further provide a method for increasingthe fluorous nature of an organic compound by reacting it with at leastone second compound (IV), where component X in fluorous compound (IV)may be —SO₃H. The resultant compounds are fluorous benzene sulfonicacids that have uses including, but not limited to, scavenging amines,alcohols and other nucleophiles, and/or mixtures thereof.

[0165] In the present method, when component X of fluorous compound (IV)is as described above, the organic compounds that are reacted withfluorous compound (IV) can be separated from the reaction mixture by aseparation technique that may include a standard or fluorous separationtechnique known to those skilled in the art. In the method wherefluorous compound (IV) is to be used as a fluorous tagging reagent, forexample fluorous benzyloximes, fluorous benzoyl chlorides, fluorousbenzenesulfonyl chlorides, or fluorous phenols, then the tagged organiccompound may be subjected to subsequent chemical transformations.

[0166] In addition, the method of the present invention may furtherinclude reducing the fluorous content of a second fluorous-taggedorganic compound that is tagged with fluorous compound (IV). In thisaspect of the invention, the first fluorous-tagged organic compound, inwhich the tag is from fluorous compound (IV), is subjected to at leastone chemical reaction and potentially at least one purification process.The chemical reaction(s) produces the second fluorous-tagged organiccompound, in which the tag is from fluorous compound (IV), which isisolated and subjected to the fluorous content reducing step. Theresultant molecules may have uses that include, but are not limited to,pharmaceutical compounds or intermediates, and combinatorial librarycomponents.

[0167] The fluorous nature of the second fluorous-tagged organiccompound may be reduced by removing at least one grouping of atomshaving the possible structure: —C₆H_(5-m)—[W_(p)(CH₂)_(n)R_(f)]_(m),—[W_(p)(CH₂)_(n)R_(f)]_(m), —(CH₂)_(n)R_(f), and R_(f) from the secondfluorous tagged organic compound.

[0168] In still a further embodiment, the present invention providescompounds for increasing the fluorous nature of an organic compoundhaving the general structure of:

X—(CH₂)_(n)R_(f)  (V)

[0169] wherein R_(f) is a fluorous group and n is an integer from 0 to5. X may be a grouping of atoms having the substructure of —C(CH₃)₂COCl.The resultant compounds are fluorous pivaloyl chlorides. Fluorouspivaloyl chlorides have uses including, but not limited to, the taggingof alcohols and amines, and/or mixtures thereof. The fluorous taggedorganic compound can then be separated from the reaction mixture by aseparation technique that may include a standard or fluorous separationtechnique known to those skilled in the art. The tagged compound maythen be subjected to subsequent chemical transformations.

[0170] Fluorous reagents such as (V), where component X is —C(CH₃)₂COCl,may be prepared by one of various schemes that employ a combination oforganic techniques. For example, one possible scheme for the preparationof fluorous pivaloyl chlorides is disclosed in Scheme 29.

[0171] The present invention also provides a method for increasing thefluorous nature of an organic compound, including the step of reactingthe organic compound with at least one second compound having thegeneral structure of fluorous compound (V), as described above and alsoincluding where component X of fluorous compound (V) may be the group—CR⁴⁵R⁴⁶SH, —CR⁴⁵R⁴⁶SR⁴⁷, —SO₂Cl, —OC(═O)NHNH₂, —NHC(═NH)NH₂, —SO₂NH₂,—SO₂NHNH₂, —NCZ, -maleimide, -α-succinic anhydride, or —COCH₂COR⁴⁸. R⁴⁵,R⁴⁶, R⁴⁷, and R⁴⁸ are independently, the same or different, hydrogen,linear alkyl, branched alkyl, benzyl, or CH₂)_(n)R_(f) and Z is eitheroxygen or sulfur. The organic compound has at least one functional groupthat reacts with group X on at least one second fluorous compound (V) toform at least one chemical bond between the organic compound and atleast one second compound (V). The chemical reaction results in a firstfluorous tagged organic compound with an increased fluorous naturerelative to the fluorous nature of the organic compound. The increasedfluorous nature of the first fluorous tagged organic compound enablesseparating the first fluorous tagged organic compound from othercompounds by use of separation techniques that may include standard orfluorous separation techniques known to those of ordinary skill in theart. The tagged compound may then be subjected to subsequent chemicaltransformations.

[0172] The present invention may also provide a method for increasingthe fluorous nature of an organic compound by reacting it with at leastone second compound (V), where component X in fluorous compound (V) is—CR⁴⁵R⁴⁶SH where the groups R⁴⁵ and R⁴⁶ are defined above. The resultantstructures are fluorous alkylthiols. Fluorous alkylthiols have usesincluding, but not limited to, tagging/scavenging numerous electrophiliccomponents, for example, aryl halides, bromomethylcarbonyl compounds,benzyl halides, allyl halides and other electrophiles, and/or mixturesthereof. They can also be used in the scavenging of metals such as Ni,Pd, and the like.

[0173] The present invention may also provide a method for increasingthe fluorous nature of an organic compound by reacting it with at leastone second compound (V), where component X in fluorous compound (V) is—CR⁴⁵R⁴⁶SR⁴⁷, where the groups R⁴⁵, R⁴⁶ and R⁴⁷ are defined above. Theresultant compounds are fluorous alkyl sulfide reagents. Fluorous alkylsulfide reagents have potential application including, but not limitedto, scavenging oxidation agents and carbocations, for example,carbocations produced in peptide deprotection reactions.

[0174] The present invention may also provide a method for increasingthe fluorous nature of an organic compound by reacting it with at leastone second compound (V), where component X in fluorous compound (V) is—SO₂Cl. The resultant compounds are fluorous alkylsulfonyl chloridesthat have uses including, but not limited to, tagging and scavengingalcohols, amines, thiols and other nucleophiles, and/or mixturesthereof.

[0175] The present invention may further provide a method for increasingthe fluorous nature of an organic compound by reacting it with at leastone second compound (V), where component X in fluorous compound (V) is—OC(═O)NHNH₂. The resultant compounds are fluorous alkylcarbazates thathave uses including, but not limited to, tagging ketones.

[0176] The present invention may also provide a method for increasingthe fluorous nature of an organic compound by reacting it with at leastone second compound (V), where component X in fluorous compound (V) is—NHC(═NH)NH₂. The resultant compounds are fluorous alkylguanidines thathave uses including, but not limited to, acting as strong organic baseswhich can scavenge acid.

[0177] The present invention may further provide a method for increasingthe fluorous nature of an organic compound by reacting it with at leastone second compound (V), where component X in fluorous compound (V) is—SO₂NH₂. The resultant structures are fluorous alkyl sulfonamides thathave uses including, but not limited to, scavenging acids, acidchlorides, anhydrides, isocyanates, isothiocyanates, chloroformates andother electrophiles, and/or mixtures thereof.

[0178] The present invention may also provide a method for increasingthe fluorous nature of an organic compound by reacting it with at leastone second compound (V), where component X in fluorous compound (V) is—SO₂NHNH₂. The resultant structures are fluorous alkylsulfonylhydrazides. Fluorous alkyl sulfonylhydrazides have usesincluding, but not limited to, scavenging aldehydes and ketones and/ormixtures thereof.

[0179] The present invention may further provide a method for increasingthe fluorous nature of an organic compound by reacting it with at leastone second compound (V), where component X in fluorous compound (V) is—NCZ, where Z is either oxygen or sulfur. The resultant compounds arefluorous alkyl isocyanates or fluorous alkyl isothiocyanates that haveuses including, but not limited to, scavenging amines, hydrazines andother nucleophiles, and/or mixtures thereof.

[0180] The present invention may also provide a method for increasingthe fluorous nature of an organic compound by reacting it with at leastone second compound (V), where component X in fluorous compound (V) is-maleimide. The resultant compounds are fluorous maleimides that has theuses including, but not limited to, scavenging primary and secondaryamines and thiols, and/or mixtures thereof.

[0181] The present invention may further provide a method for increasingthe fluorous nature of an organic compound by reacting it with at leastone second compound (V), where component X in fluorous compound (V) is-α-succinic anhydride. The resultant fluorous succinic anhydride hasuses including, but not limited to, scavenging amines.

[0182] The present invention may also provide a method for increasingthe fluorous nature of an organic compound by reacting it with at leastone second compound (V), where component X in fluorous compound (V) is—COCH₂COR⁴⁸, wherein R⁴⁸ is defined above. The resultant fluorousalkyl-1,3-diketone has uses including, but not limited to, scavengingprimary amines in the presence of secondary amines.

[0183] In the present method, when component X of fluorous compound (V)is as described above, the organic compounds that are reacted withfluorous compound (V) can be separated from the reaction mixture by aseparation technique that may include a standard or fluorous separationtechnique known to those skilled in the art. In the method wherefluorous compound (V) is to be used as a fluorous tagging reagent, forexample fluorous pivaloyl chlorides, fluorous alkylthiols, fluorousalkylsulfonyl chlorides, or fluorous alkylcarbazates, then the taggedorganic compound may be subjected to subsequent chemicaltransformations.

[0184] In addition, the method of the present invention may furtherinclude reducing the fluorous content of a second fluorous-taggedorganic compound that is tagged with fluorous compound (V). In thisaspect of the invention, the first fluorous-tagged organic compound, inwhich the tag is from fluorous compound (V), is subjected to at leastone chemical reaction and potentially at least one purification process.The chemical reaction(s) produces the second fluorous-tagged organiccompound, in which the tag is from fluorous compound (V), which isisolated and subjected to the fluorous content reducing step. Theresultant molecules may have uses that include, but are not limited to,pharmaceutical compounds or intermediates, and combinatorial librarycomponents.

[0185] The fluorous nature of the second fluorous-tagged organiccompound may be reduced by removing at least one grouping of atomshaving the possible structure: —C₆H_(5-m)—[W_(p)(CH₂)_(n)R_(f)]_(m),—[W_(p)(CH₂)_(n)R_(f)]_(m), —(CH₂)_(n)R_(f), and R_(f) from the secondfluorous tagged organic compound.

[0186] In still another embodiment, the present invention providescompounds for increasing the fluorous nature of an organic compoundhaving the general structure of:

[0187] wherein R_(f), R_(f)′, and R_(f)″ are each fluorous groups,R_(f)′″ is a perfluoroalkyl group of 8 to 16 carbon atoms, X and X′ areleaving groups, m is an integer from 1 to 5, m′, m″, n, n′, and n″ areeach integers from 0 to 5, m′″ is an integer from 0 to 4, and p, p′, andp″ are each either 0 or 1. W, W′ and W″ are each an atom or groupingatoms having the formula O, S, NR⁴⁹, CR⁵⁰R⁵¹, or SiR⁵²R⁵³. R⁴⁹, R⁵⁰, andR⁵¹ are independently, the same or different, either hydrogen, linearalkyl, branched alkyl, aryl, benzyl or —(CH₂)_(n′″)R_(f). R⁵² and R⁵³are independently, the same or different, either hydrogen, linear alkyl,branched alkyl, aryl, benzyl or —(CH₂)_(n′″)R_(f) and n′″ is an integerfrom 0 to 5.

[0188] In the present invention, the leaving group X in structure (VI)may be various leaving groups suitable for use in the present inventionand known to those skilled in the art. X may be a leaving group with astructure consisting of a halide, —N₃, —CN, —OR³⁰, —ONH₂, —ONHR³⁰,—ONR³⁰ ₂, O₂CR³⁰, —O₂COR³⁰, —O₂CNR³⁰ ₂, —SR³⁰, —OC(S)R³⁰, R³⁰CS₂—,—SC(O)SR³⁰, —SCS₂R³⁰, —OC(O)SR³⁰, —OC(S)OR³⁰, —SC(S)OR³⁰, R³⁰SO₂—,R³⁰SO₃—, R³⁰OSO₂—, R³⁰OSO₃—, R³⁰PO₃—, R³⁰OPO₃—, an N-imidazolyl group,an N-triazolyl group, an N-benzotriazolyl group, a benzotriazolyloxygroup, an imidazolyloxy group, an N-imidazolinone group, anN-imidazolone group, an N-imidazolinethione group, an N-succinimidylgroup, an N-phthalimidyl group, an N-succinimidyloxy group, anN-phthalimidyloxy group, —ON═C(CN)R³⁰, or a 2-pyridyloxy group, whereinR³⁰ is one of linear alkyl, branched alkyl, aryl, benzyl, or—(CH₂)_(n″)R_(f), wherein n″ in an integer from 0 to 5.

[0189] In the present invention, the leaving group X′ in structure (VII)may be a leaving group that is a halide, methane sulfonate,p-toluenesulfonate, trifluoromethanesulfonate orperfluoroalkylsulfonate.

[0190] The present invention also provides a method for increasing thefluorous nature of an organic compound, including the step of reactingthe organic compound with at least one second compound having thegeneral structure of fluorous compound (VI), (VII), (VIII), or (IX) asdescribed above, to create a first fluorous tagged organic compound. Theorganic compound having at least one functional group reactive with thefunctionality on the second fluorous compound (VI), (VII), (VIII), or(IX) forming at least one chemical bond between the organic compound andthe second fluorous compound (VI), (VII), (VIII), or (IX) resulting inthe first fluorous tagged organic compound. The fluorous nature of thefirst fluorous tagged organic compound is increased relative to theorganic compound to enable separation of the first fluorous taggedorganic compound from at least one other compound by using separationtechniques that may include standard or fluorous separation techniquesknown to those of ordinary skill in the art.

[0191] In addition, the method of the present invention may furtherinclude reducing the fluorous content of a second fluorous-taggedorganic compound that is tagged with fluorous compound (VI), (VII),(VIII), or (IX). In this aspect of the invention, the firstfluorous-tagged organic compound, in which the tag is from fluorouscompound (VI), (VII), (VIII), or (IX), is subjected to at least onechemical reaction and potentially at least one purification process. Thechemical reaction(s) produces the second fluorous-tagged organiccompound, in which the tag is from fluorous compound (VI), (VII),(VIII), or (IX), which is isolated and subjected to the fluorous contentreducing step. The resultant molecules may have uses that include, butare not limited to, pharmaceutical compounds or intermediates, andcombinatorial library components.

[0192] Fluorous Compounds and Their use as Fluorous Tags

[0193] In the method of the present invention, the fluorous compoundsdescribed above may be used as fluorous tags to increase the fluorousnature of an organic compound. The tagged organic compound can then besubjected to subsequent chemical transformations andseparations/purifications. Representative demonstrations of the fluoroustagging process is described below.

[0194] In one demonstration of its utility as a tag in fluoroussynthesis, a fluorous thiol 1H,1H,2H,2H-perfluorodecanethiol wasattached to the electron deficient 2,4-dichloro-6-methylpyrimidine by anucleophilic substitution in the presence of diisopropylethylamine(DIPEA) (Scheme 30).

[0195] Two regioisomers 1a and 1b were generated in a ratio of 3:1 byHPLC analysis. If polymeric tags were used, regioisomers like 1a and 1bcould not be separated. However, fluorous compounds 1a and 1b werereadily separated by flash column chromatography on normal silica gelbased on their different polarity. The major isomer 1a was used forfurther nucleophilic substitution with 3-(trifluoromethyl)-pyrazole togive 2 (Scheme 31). The fluorous sulfur tag was then activated byoxidation with Oxone® followed by the displacement with ten assortednucleophiles including primary and secondary amines and thiols to yielddisubstituted pyrimidines 4 (Table 1). Oxone® is commercially availablefrom E. I. du Pont de Nemours and Company. Results were excellent:yields of 4a-j ranged from 74-96% and purities were usually above 90%.

[0196] An important feature of fluorous synthesis is the employment ofsimple solid-phase extraction (SPE) over FluoroFlash® cartridges chargedwith fluorous silica that has a perfluorocarbon bonded-phase toselectively retain fluorous molecules while organic compounds passthrough as fast as the solvent front. Only two fractions need to becollected from the SPE; a MeOH/H₂O (80/20) fraction containingnon-fluorous compounds and a MeOH fraction containing fluorouscompounds. The strong fluorine-fluorine interaction retains smallmolecules tagged with a light fluorous tag (C₈F₁₇) on fluorous silicagel until elution with a stronger solvent such as MeOH. Fluorousintermediate 2 was purified by SPE and collected from the MeOH fraction,while product 4 was collected from the MeOH/H₂O fraction. The DIPEA usedfor the reaction of 1a can be removed by acidic workup prior to SPE. Thecrude product containing cleaved tag, DIPEA, and excess nucleophile waspurified by loading onto a FluoroFlash™ cartridge with a small amount ofweak acidic ion exchange resin (Amberlite™ CG-50) on top of the fluoroussilica and eluted with MeOH/H₂O (80/20). TABLE 1 Structures, yields, andpurities of distributed pyrimidinates 4a-j entry nucleophile equivproduct yield (purity)^(a) 1

2.5 4a 96% (97%) 2

2.0 4b 91% (93%) 3

2.0 4c 82% (92%) 4

2.5 4d 93% (90%) 5

2.5 4e 79% (90%) 6

1.2 4f 88% (89%) 7

1.2 4g 74% (93%) 8

1.0 4h 76% (97%) 9

1.0 4i 84% (92%) 10

1.0 4j 77% (90%)

[0197] The cleaved tag was retained by the fluorous silica and amineswere retained by the ionic exchange resin. It was found that CF₃ groupof products 4 did not hold the molecules against elution with MeOH/H₂O.Most products had purities greater than 90% after SPE. The crudeintermediate 2 was separated from the excess 3-(trifluoromethyl)pyrazoleby collecting the MeOH fraction. The crude product 4e containing excess4-phenylpiperazine, DIPEA, and cleaved fluorous tag was purified bycollecting the MeOH/H₂O fraction from a cartridge charged with fluoroussilica and acidic ion exchange resin.

[0198] Synthesis of substituted pyrimidines exemplifies the uniquecharacters of fluorous synthesis, including the use of tag strategy forquick SPE, analysis and separation of tagged-isomers by conventionaltools, and adaptability of traditional solution-phase reactionconditions. The “beadless” and traceless fluorous thiol tag iscomplementary to corresponding thiol linkers in solid-phase synthesis.The “catch and release” method with the fluorous thiol can be applied tothe synthesis of other substituted N-heterocyles.

[0199] In another example of the method of the present invention,wherein the fluorous compounds may be used as an alternative to apolymer resin to prepare libraries of organic compounds. Below is anexample demonstrating the utility of a perfluoroalkylsulfanylphenol as afluorous tag.

[0200] Described in this paper is the synthesis of fluorous version ofMarshall resin, perfluoroalkylsulfanylphenol 5 (FluoMar™). FluoMar isnow commercially available from Fluorous Technologies Inc. (Pittsburgh,Pa.). The utility of this compound is illustrated by the solution-phasesynthesis of amides and diamides.

[0201] The FluoMar™ 5 was readily prepared by S-alkylation of4-mercaptophenol with C₈F₁₇CH₂CH₂₁ and purified by flash columnchromatography on normal silica gel (Scheme 32). The ethylene spacerbetween the C₈F₁₇ tag and the sulfur is expected to minimize the strongelectron-withdrawing effect from the perfluoroalkyl group and maintainthe nucleophilicity of the hydroxy group. This compound has the generalfeatures of organic molecules; it dissolves well in common solvents suchas CH₂Cl₂, THF, and AcOEt, and can be analyzed by traditionalchromatographic and spectroscopic methods.

[0202] With compound 5 in hand, we first validated the attachment tocarboxylic acids 6 and the tag cleavage by the amine displacement(Scheme 33). The coupling of 5 with indole-5-carboxylic acid 6{1} (2.0equiv) or 7-methoxy-2-benzofurancarboxylic acid 6{2} was carried outunder a standard solution-phase conditions with 2.0 equiv ofdiisopropylcarbodiimide (DIC) and 1.0 equiv of dimethylaminopyridine(DMAP) in DMF. These intermediates were purified by regular flash columnchromatography. Compounds 7{1} and 7{2} were each split to threeportions and directly displaced with three primary amines 8{1-3} withoutoxidation of the sulfur to give the corresponding amides 9{1-2,1-3}.After a quick acidic workup with 1.0 N HCl to remove the unreactedamine, the crude product was loaded onto a FluoroFlash™ cartridge andthe MeOH/H₂O fraction was collected to give analytically pure product.The FluoMar™ tag 5 was recovered in the MeOH fraction in 65-70% yield.

[0203] Encouraged by the preliminary results, the use of FluoMar™ 5 in amulti-step parallel synthesis of diamides was explored (Scheme 34). TheN-Boc isonipecotic acid 10 was coupled with 5 followed by deprotectionwith TFA and N-acylation with three different acid halides. Theresulting compounds 12{1-3} were each split into three portions anddisplaced by three amines resulting in a demonstration library ofdiamides 13{1-3,1-3}. The final products were purified by SPE andcleaved FluoMar™ 5 was recovered in an average yield of 65%.

[0204] Fluorous Compounds and Their use as Fluorous Scavengers

[0205] In a further example of the method of the present invention,wherein the fluorous compounds described above may be used react withunreacted reaction components, thereby tagging the unreacted component.The tagged unreacted reaction component can then be readily removed orscavenged from the reaction mixture by a separation technique that mayinclude a standard or fluorous separation technique known to thoseskilled in the art. A representative demonstration of the fluorousscavenging process is described below.

[0206] Introduced herebelow are two new fluorous electrophilicscavengers, isatoic anhydride 14 and isocyanate 15, that can be used toremove primary and secondary amines from the reaction mixtures.

[0207] Compound 15 was readily prepared by N-alkylation of isatoicanhydride with C₈F₁₇CH₂CH₂CH₂I using sodium hydride as a deprotonationagent. The C-4 carbonyl is an active site for the nucleophilic attack.Fluorous isocyanate 15 was synthesized following a literature procedure.To demonstrate the utility of these two compounds as scavengers foramines, two substrates, phenyl isocyanate and phenyl isothiocyanate werereacted with various primary and secondary amines to producecorresponding ureas and thioureas (Scheme 35). In each case, 1.5 equivof amine was used to ensure the consumption of the substrate.

[0208] Upon completion of the reaction (as monitored by TLC or HPLC),1.0 equiv of fluorous scavenger was added to react with the excessamine. The reaction mixture was then loaded onto a FluoroFlash®cartridge charged with fluorous silica. The cartridge was eluted withMeOH—H₂O (80:20) to collect the product fraction and then with 100% MeOHto wash off the fluorous scavenged product and the unreacted scavenger.Results listed in Table 2 demonstrate that the product purity is greaterthan 95% after the scavenging. Use of fluorous isatoic anhydride 14 asscavenger usually give better yields (75-100%) than that of isocyanate15 (34-100%).

[0209] Fluorous isatoic anhydride 14 was further evaluated in thereaction of epoxide 18 with amines (Scheme 36). In a high loadingexperiment using 2.0 equiv of amine and 3.0 equiv of scavenger 14,products 19a (42%) and 19b (67%) from primary amines had better yieldsthan products 19d (15%) and 19e (29%) from secondary amines. It washypothesized that the low yield might have been caused by theinteraction of excess scavenger with the β-hydroxyamine product. TABLE 2Structures, yields, and purities of ureas and thioureas^(a) substrateamine scavenger product X yield purity^(b) 16a 16b 16a 16b

14 14 15 15

O S O S 100% 75% 52% 98% >95% 95% 95% 95% 16a 16b 16a 16b

14 14 15 15

O S O S 100% 72% 100% 80% >95% >95% >95% >95% 16a 16b 16a 16b

14 14 15 15

O S O S 100% 95% 100% 34% >95% >95% 95% 95% 16a 16b 16a 16b

14 14 15 15

O S O S 100% 100% 100% 68% >95% 95% 95% >95% 16a 16b 16a 16b

14 14 15 15

O S O S 100% 100% 100% 96% >95% 95% 95% 95%

[0210] To test this hypothesis, reactions with lower input of thesecondary amine (1.5 equiv) and scavenger (0.7 equiv) were performed.Significant yield improvement was observed for 19d (62%) and 19e (58%)(Table 3). However, under both reaction conditions, no clean desiredproduct 19c was isolated. It was contaminated with the di-N-alkylationproduct. All other cases listed in Table 3, the product yields may varyin a broad range under different reaction conditions, the purities wereconsistently between 90-95%.

TABLE 3 Structures, yields, and purities of β-hydroxyamines^(a)scavenger 14 amine (equiv) (equiv) product yield purity^(b)

2.0 3.0

42% 95%

2.0 3.0

67% 95%

2.0 1.5 3.0 0.7

0% 0% ——

2.0 1.5 3.0 0.7

15% 62% >95% >95%

2.0 1.5 3.0 0.7

29% 58% 90% 90%

[0211] Fluorous Compounds and Their use as a Protecting Group: Taggingand Detagging of an Organic Compound

[0212] The method of the present invention can further be demonstratedby the use of a fluorous compound as a protecting group for an organicfunctional group. The tagging (protection) and detagging (deprotection)of an organic compound is demonstrated below using an F-Fmoc tag.

[0213] Protection of Amine with of F17-Fmoc.

[0214]N-[2-(1H,1H,2H,2H-Perfluorodecyl)fluorenyl-9-methoxycarbonyloxy]-1,2,3,4-tetrahydroquinoline:To a solution ofN-[2-(1H,1H,2H,2H-Perfluorodecyl)fluorenyl-9-methoxycarbonyloxy]succinimide(F17-Fmoc-OSu) (78.3 mg, 0.1 mmol) in THF was added1,2,3,4-tetrahydroisoquinoline (15.0 mg, 0.12 mmol) at 23° C. After 10min, the solvent was removed under reduced pressure, and the residue wasdissolve in THF (1 mL). The solution was loaded onto a FluoroFlash® SPEcartridge (5 g), and it was eluted with MeOH—H₂O (80:20, 15 mL), andthen with MeOH (20 mL). The methanol fraction was collected, and thesolvent was removed under reduced pressure to give the title compound aswhite solid (69.4 mg, 84% yield). ¹H NMR (270 MHz, CDCl₃) δ 7.90-7.02(11H, m), 7.64 (2H, d, J=13 Hz), 4.50 (2H, d, J=12 Hz), 4.27 (1H, t, J=7Hz), 3.72 (2H, bd), 2.98 (2H, bs), 2.86 (2H, bs), 2.55-2.25 (2H, m); MSAPCI positive, m/z=802 [m⁺H]⁺.

[0215] Deprotection of F17-Fmoc Group.

[0216] Deprotection of F17-Fmoc protected amine was performed accordingto standard conditions. (Morpholine-THF, 1:4). Reaction time istypically within 15 min at 23° C., affording1,2,3,4-tetrahydroisoquinoline.

[0217] The present invention will be described further by reference tothe following examples. The following examples are merely illustrativeof the invention and are not intended to be limiting. Unless otherwiseindicated, all parts are by weight.

EXAMPLES Example I

[0218] Preparation ofN-[4-(1H,1H,2H,2H-perfluorodecyl)benzyloxycarbonyloxy]succinimide

[0219] Under dry N₂ atmosphere at 0° C., phosgene (21.5 mL; 20% intoluene) was charged to a 250 mL 3-neck flask equipped with thermometer,N₂ gas inlet, and addition funnel. A solution of 4-(1H,1H,2H,2H-perfluorodecyl)benzyl alcohol (15.0 g) in anhydrous THF (75 mL)was added dropwise, keeping the temperature between 0-5° C. The mixturewas stirred at 0-5° C. until the reaction was complete. The solvent andexcess phosgene were removed in under vacuum and the product wasdissolved in chloroform (200 mL). N-hydroxysuccinimide dicyclohexylaminesalt (8.81 g) was added portionwise over 5-10 minutes. After thereaction was complete, water (100 mL) and 1 N HCl (100 mL) were added,and the product was extracted with chloroform (3×100 mL). The organiclayers were dried over MgSO₄, filtered and concentrated. The crudeproduct was recrystallized in hot methanol (900 mL). The solid wascollected by filtration and dried under high vacuum for 5 h to givedesired product (15.4 g, 82% yield). The structure of the product wascharacterized ¹H NMR.

Example II

[0220] Preparation 4-[3-(perfluorooctyl)propyloxy]benzaldehyde

[0221] A 500 mL 2-neck flask equipped with thermometer and gas inletcharged with potassium carbonate (27.6 g), hydroxy benzaldehyde (13.4g), and 3-(perfluorooctyl)propyl iodide (58.8 g) in DMF (200 mL) washeated to 65° C. (internal temperature). The mixture was stirred at 65°C. until the reaction was complete. The reaction mixture was cooled toroom temperature. Water (300 mL) and ether (300 mL) were added and themixture stirred vigorously for 5 min. The layers were separated and theorganic layer retained. The aqueous layer was extracted with ether(3×200 mL). The combined organic layers were washed with water (2×100mL), Na₂S₂O₃ (1×100 mL), 2.5 N NaOH (3×100 mL), and aqueous NaCl (1×100mL). The organic layer was dried over MgSO₄, filtered and concentrated.The product was further dried under high vacuum for 5 h to give desiredproduct (53 g, 91% yield). The structure of the product wascharacterized ¹H NMR.

Example III

[0222] Preparation of Fluorous Fmoc-OSu

[0223] To a suspension of 2-aminofluorene (10.3 g) in fluoroboric acid(50% in water, 100 mL) was slowly added a solution of NaNO₂ (4.4 g) inwater (15 mL) at below 10° C. The mixture was stirred for 6 h at below10° C. The precipitate was collected by filtration, and was washed withice-cooled water (3×), and was dried under air for 12 h to giveyellow-green-brownish powder (17.0 g) that was used for the next stepwithout purification.

[0224] To a suspension of crude fluorene-2-diazonium tetrafluoroborate(17.0 g) in MeOH (100 mL) was added Pd(OAc)₂ (0.14 g, 0.62 mmol) underan nitrogen atmosphere. The mixture was warmed to 30° C. (internaltemperature), and then 1H,1H, 2H-perfluorodec-1-ene (32.0 g) was addeddropwise to keep the temperature below 45° C. The mixture was stirred at45° C. for 2 h, and then it was refluxed for 1 h. After cooling to roomtemperature, Et₂O (200 mL) and H₂O (200 mL) were added. After theseparation, the aqueous layer was extracted with Et₂O (2×100 mL). Theether layers were combined, and were washed with 1 N HCl (2×), water (2x), and brine (1×). The mixture was dried over MgSO₄. After filtration,it was treated with charcoal (2 scoops). The charcoal was filtered offby passing though a Celite® pad. Celite® is commercially available fromWorld Minerals Inc. (Lompoc, Calif.). After the removal of the solvent,light orange powder was obtained (31.5 g, 91% yield based on2-aminofluorene).

[0225] Under an nitrogen atmosphere, Pd/C (10 wt % on active carbon, 1.0g, loading=2 mol %) was added to a solution of2-(1H,2H-perfluorodec-1-enyl)fluorine (31.5 g, 51.6 mmol) in THF (600mL) and MeOH (100 mL). The mixture was stirred under a hydrogen (1 atm)for 1 day at 23° C. The catalyst was removed by filtration through a padof Celite® under a nitrogen atmosphere, and the Celite® was rinsed withTHF (4×50 mL). The filtrate was concentrated to give white powder (30.0g, 95% yield).

[0226] To a suspension of NaH (60 wt % in mineral oil, 2.3 g) in Et₂O(200 mL) was added 2-(1H,1H, 2H,2H-perfluorodecyl)fluorene (7.4 g) andethyl form ate (19.0 mL) under an nitrogen atmosphere. The mixture wasrefluxed for 3 h, and then cooled on ice-water bath. Aquous HCl (1 N,200 mL) was slowly added, and the two layers were separated. The aquouslayer was extracted with Et₂O (1×50 mL). The ether layers were combined,and were washed with brine (2×). After being dried over MgSO₄, thesolvent was removed to give yellow solid. The solid was dissolved inTHF-MeOH (1:1, 200 mL), and NaBH₄ (1.2 g) was added in small portionsover the period of 1.5 h at 6° C. After 2 h, aqueous HCl (1 N, 200 mL)and Et₂O (100 mL) were added. The aqueous layer was extracted with Et₂O(1×100 mL). The ether layers were combined, and were washed with 1 N HCl(1×) and brine (1×). After being dried over MgSO₄, the solvent wasremoved under reduced pressure. The product was purified by flashchromatography (SiO₂, eluent: hexanes/EtOAc=9:1-4:1) to give the titlecompound (6.2 g, 81% yield).

[0227] Phosgene (20 wt % solution in toluene, 2.3 mL, 4 mmol) was addedto a solution of 9-[2-(1H,1H,2H,2H-perfluorodecyl)fluorenyl]methanol(1.3 g) in THF (60 mL) at 8° C. The mixture was stirred at 23° C. for 15h, and the solvent was removed under reduced pressure to form paleyellow solid. The solid was dissolved in THF (30 mL), and NaOSu (0.54 g)was added in two portions over the period of 2 h. The mixture wasvigorously stirred for 1 d at 23° C. Et₂O (50 mL) was added, and themixture was filtered through a pad of Celite®. The Celite® pad wasrinsed with Et₂O (3×10 mL). The filtrates were combined, and the solventwas removed under reduced pressure to give the product as white powder(1.5 g, 95% yield). ¹H NMR (270 MHz, CDCl₃) δ7.75 (2H, t, J=8.3 Hz),7.62 (1H, d, J=7.4 Hz), 7.5 (1H, s), 7.44 (1H, t, J=7.5 Hz), 7.39-7.27(2H, m), 4.67-4.50 (2H, m), 4.34 (1H, t, J=7.4 Hz), 3.10-2.95 (2H, m),2.85 (s, 4H), 2.55-2.32 (2H, m); MS APCI negative, m/z=782 [m−H]−, 654,641, 611.

Example IV

[0228] Preparation of p-(1H,1H,2H,2H-perfluorodecanesulfanyl)phenol.

[0229] To a solution of 4-mercaptophenol (5.05 g) in THF (60 ml) wasadded Et₃N (11.1 mL) and 1H,1H,2H,2H-perfluorodecaneiodide (23.8 g). Thereaction mixture was heated at 80° C. for 8 h. The reaction mixture wasthen poured into ice water. The precipitate was filtered off, washedwith hexanes and dried under vacuum to provide the desired product 1 asa white solid (18.0 g, 78% yield), mp 85-87° C. ¹H NMR (300 MHz, CDCl₃)δ7.38 (d, J=8.8 Hz, 2H), 6.86 (d, J=8.8 Hz, 2H), 5.0 (br s, 1H),3.06-3.00 (m, 2H), 2.56-2.39 (m, 2H). LC-MS (EI) m/z (rel. intensity)572 (M⁺), 553 (X), 169 (V), 139 (70), 125 (100), 97 (23), 81 (20), 69(45), 58 (55). HRMS calc'd for C₁₆H₉F₁₇S 572.0093; found 572.0093.

[0230] Fluorous Synthesis Usingp-(1H,1H,2H,2H-perfluorodecanesulfanyl)phenol as a tag.

[0231] To a mixture of p-(1H,1 H,2H,2H-perfluorodecanesulfanyl)phenol(2.2 g), N-Boc isonipecotic acid (1.76 g) in DMF (6 mL) was dissolveddimethylaminopyridine (DMAP) (0.05 g) and N,N′-diisopropylcarbodiimide(DIC) (1.2 ml). After stirring at room temperature for 1.5 h, thereaction mixture was poured into water and extracted with EtOAc. Theorganic layers was washed with brine, dried over MgSO₄, and filtered.The concentrated crude product was purified by flash columnchromatography with EtOAc/hexanes (15/85) to give the fluorous boundN-Boc isonipecotic ester (2.13 g, 71% yield), mp 94-95° C. ¹H NMR (300MHz, CDCl₃) δ7.39 (d, J=8.6 Hz, 2H), 7.07 (d, J=8.6 Hz, 2H), 4.13-4.06(m, 2H)), 3.13-3.07 (m, 2H), 2.97-2.88 (m, 2H), 2.76-2.69 (m, 1H),2.42-2.37 (m, 2H), 2.07-2.01 (m, 2H), 1.84-1.71 (m, 2H), 1.47 (s, 9H).LC-MS (EI) m/z (rel. intensity) 783 (M⁺), 764 (VIII), 710 (35), 682(40), 572 (60), 212 (50), 156 (100), 112 (32), 77 (IX). HRMS calc'd forC₂₇H₂₆O₄F₁₇SN 783.1286; found 783.1286.

[0232] To a solution of fluorous bound N-Boc isonipecotic ester (7.22 g)in CH₂Cl₂ (15 mL) was added TFA (6.5 mL) in 2 portions of 3.25 ml ininterval of 4 h. After 10 h, the reaction mixture was poured onto icewater (100 mL), aquous NaHCO₃ (200 mL) was added and the mixture wasstirred for 20 min. The white precipitate was filtered, washed withwater and dried under vacuum. Quantitative yield of fluorous boundisonipecotic ester was obtained (6.3 g, 100% yield), mp 147-148° C. Thiscompound was used for next step without further purification. ¹H NMR(300 MHz, CD₃OD) δ7.47 (d, J=8.8 Hz, 2H), 7.13 (d, J=8.8 Hz, 2H),3.48-3.41 (m, 2H), 3.31-3.29 (m, 1H), 3.19-3.16 (m, 4H); 3.10-2.98 (m,1H); 2.54-2.27 (m, 4H); 2.07-1.93 (m, 2H). LC-MS (EI) m/z (rel.intensity) 682 (M⁺, 25), 664 (30), 572 (22), 139 (VII), 112 (100), 84(30). HRMS calc'd for C₂₄H₁₈O₂F₁₇SN 682.0722; found 682.0722.

[0233] To a solution of fluorous bound isonipecotic ester (2.0 g) in THF(10 mL) was added Et₃N (1.2 mL) followed by 4-chlorobenzoyl chloride(617 μL). The mixture was heated at 50-60° C. for 2.5 h. The reactionmixture was poured onto 1N HCl aq and extracted with EtOAc. The organiclayer was washed with brine, dried over MgSO₄, and filtered. Theconcentrated crude product was purified by column chromatography withEtOAc/hexanes (30/70) to provide fluorous bound N-acylated isonipecoticester 5 (1.9 g, 79%), mp 92-94° C. ¹H NMR (300 MHz, acetone d-₆) δ 7.50(d, J=8.5 Hz, 2H), 7.47 (s, 4H), 7.16 (d, J=8.5 Hz, 2H), 3.27-3.21 (m,2H), 3.15 (br s, 1H), 3.02-2.93 (m, 1H), 2.62-2.47 (m, 2H); 1.85-1.73(m, 2H). LC-MS (EI) m/z (rel. intensity) 821 (M⁺, 33), 802 (16), 682(15), 572 (25), 250 (35), 222 (15), 156 (16), 139 (85), 121 (100), 69(23). HRMS calc'd for C₂₉F₁₇H₂₁NSO₃Cl 821.0635, found 821.0635.

[0234] To a solution of fluorous N-acylated isonipecotic ester (0.11 g)in THF (1.0 mL) was added N-butylamine (0.02 mL). The mixture was heatedat 50-60° C. for 5 h. The reaction mixture was poured onto 1N aq HCl andextracted with EtOAc in a small vial. The organic layer was washed withbrine, dried over MgSO₄, and filtered. The concentrated oily residue(119 mg) was purified by solid-phase extraction on a 5 g FluoroFlash®fluorous silica gel cartridge eluted with MeOH/H₂O (80/20). The firstfraction (8 mL) contained the desired product was concentrated to giveproduct (40 mg, 93%). ¹H NMR (300 MHz, CDCl₃) δ7.47 (d, J=8.7 Hz, 2H),7.39 (d, J=8.7 Hz, 2H), 4.6 (br s, 1H), 3.70 (br s, 1H), 3.31-3.29 (m,1H), 3.16 (t, J=6.8 Hz, 2H); 2.90 (t, J=7.3 Hz, 1H); 2.54-2.44 (m, 1H);1.84 (br s, 2H), 1.67-1.60 (m, 2H), 1.50-1.28 (m, 4H), 0.99-0.89 (m,4H). LC-MS (EI) m/z (rel. intensity) 322 (M⁺, 30), 222 (22), 183 (63),139 (100), 128 (95), 111 (51), 82 (51), 57 (25). HRMS calc'd forC₁₇H₂₃N₂O₂Cl 322.1463, found 322.1463.

[0235] Following the general procedure described above. A 9-compounddemonstration library was synthesized by reacting of N-Boc isonipecoticacid with 3 benzoyl chlorides and 3 amines (Table 4). TABLE 4 Synthesisof isonipecotic acid derivatives nBuNH2

Example V

[0236] Fluorous Synthesis of Disubstituted Pyrimidines Using1H,1H,2H,2H-perfluorodecanethiol as the tag

[0237] To a solution of 2,4-dichloro-6-methylpyrimidine (2.1 g) andfluorous thiol (available from Fluorous Technologies, Inc. and othercommercial source, 6.1 g) in DMF (50 mL) was added diisopropylethylamine(DIPEA) (4.5 mL). After stirring at room temperature for 1 h, thereaction mixture was mixed with H₂O and then extracted with EtOAc. Theorganic layer was washed with aqueous NH₄Cl, dried out MaSO₄, andconcentrated. HPLC analysis of the crude product indicated2-chloro-4-perfluoroalkylsulfanyl-6-methylpyrimidine and4-chloro-2perfluoroalkylsulfanyl-6-methylpyrimidine (not show) in aratio about 3:1. The major isomer was isolated as a desired product (4.3g, 55% yield) using flash column chromatography on silica gel withhex:EtOAc (90:10). ¹H NMR (CDCl₃) δ2.45 (s, 3H), 2.63 (m, 2H), 3.42 (m,2H), 6.98 (s, 1H). MS m/z (rel. intensity) 606 (M⁺, 23), 368 (11), 236(VI), 187 (100).

[0238] To a solution of 2-chloro-4-alkylthio-6-methylpyrimidine (0.50 g)and 3-trifluoromethylpyrazol (0.17 g) in DMF (40 mL) was added DIPEA(217 μL) and K₂CO₃ (113 mg). After heated at 80° C. for 12 h, thereaction mixture was extracted with EtOAc, washed with aqueous NH₄Cl,dried over MgSO₄, and concentrated. The crude product was purified bysolid-phase extraction on a 5 g FluoroFlash® fluorous silica gelcartridge eluted with MeOH/H₂O (80/20) and then MeOH. The MeOH fractioncontained desired product was concentrated to givepyrozoyl-4-alkylthio-6-methylpyrimidine (0.49 g, 85%). ¹H NMR (CDCl₃)(2.57 (s, 3H), 2.74 (m, 2H), 3.47 (m, 2H), 6.74 (d, 1H), 7.23 (s, 1H),8.58 (br s, 1H). MS m/z (rel. intensity) 706 (M⁺, 30), 687 (IX), 631(X), 287 (100).

[0239] To a solution of pyrozoyl-4-alkylthio-6-methylpyrimidine (100 mg)in acetone (10 mL) was added a solution of Oxone® (350 mg) in H₂O (3 mL)at room temperature. After heating at 60° C. for 12 h, the reactionmixture with white precipitate was filtrated. The filtrate was extractedwith EtOAc, washed with brine. The organic layer was dried over MgSO₄and concentrated to corresponding sulfone (94 mg, 91%). This compoundwas used for next step reaction without further purification. ¹H NMR(CDCl₃) δ2.83 (s, 3H), 2.93 (m, 2H), 3.75 (m, 2H), 6.81 (d, 1H), 7.81(s, 1H), 8.66 (br s, 1H). MS m/z (rel. intensity) 739 (M⁺+1, 100).

[0240] To a solution of sulfone (15.0 mg) in DMF (1 mL) was addedmorpholine (5 mg). After heated at 80° C. for 10 h, the reaction mixturewas extracted with EtOAc and then washed with aqueous NH₄Cl.Concentrated crude product was purified by SPE on a 2 g FluoroFlash®cartridge eluted with MeOH/H₂O (80/20) and then MeOH. The MeOH/H₂Ofraction contained desired product was concentrated to give product (6mg, 96%). ¹H NMR (CDCl₃) δ2.50 (s, 3H), 3.72 (br m, 4H), 3.83 (m, 4H),6.33 (s, 1H), 6.69 (d, 1H), 8.61 (br s, 1H). MS m/z (rel. intensity) 314(M⁺+1, 100).

[0241] Following the fluorous tag cleavage procedure described above,the sulfone was reacted with a series of nucleophilic reagents includingprimary and secondary amines, and thiols to afford 10 disubstitutedpyrimidine analogs. The purities of the final products were greater than90% by ¹H NMR analysis.

Example VI

[0242] Preparation of Fluorous Isatoic Anhydride.

[0243] In a 2L 3-neck flask equipped with N₂ gas inlet, mechanicalstirbar, condenser, thermocouple and addition funnel, sodium hydride(7.8 g) was suspended in THF (140 ml) A solution of isatoic anhydride(29.1 g) in DMA (60 ml) and THF (100 ml) was added dropwise whilemaintaining the internal temperature below 40° C. After the addition wascomplete, DMA was added (60 ml), and the mixture was stirred at 50° C.for 45 minutes. A solution of 3-(perfluorooctyl)propyl iodide (100.0 g)in THF (100 ml) was added dropwise at 50° C. The mixture was stirred at50° C. for 12 h. The reaction was quenched with NH₄Cl (400 ml). Anextraction was performed with ethyl acetate (2×200 ml). The organiclayer was washed with H₂O (1×250 ml), dried over MgSO₄, filtered, andconcentrated. The crude product was recrystallized in warm ethyl acetate(˜250 ml), cooled slowly to room temperature, and then cooled further to0° C. overnight. The product was collected by filtration and dried underhigh vacuum for 4 h to give product (57.0 g, 54% yield).

[0244] Use of Fluorous Isatoic Anhydride as an Electrophilic Scavengerin the Preparation of 1-butyl-3-phenyl-thiourea.

[0245] To a solution of phenyl isothiocyanate (22 μL) in CH₂Cl₂ (0.5 ml)was added excess amine (30 μL). The resulting solution was stirred at60° C. on a sand bath overnight to ensure completion of the reaction.The reaction was monitored by TLC (30:70 EtOAc:hexanes). Upon completionof the reaction, Fluorous isatoic anhydride 6 was added (0.124 g) to thereaction mixture. Another 1.0 mL of CH₂Cl₂ was added to the reactionmixture to ensure complete dissolution of the solid. The reactionmixture was stirred for 2.5 h at 60° C. TLC showed the presence of thefluorous scavenger (that was added in excess), the scavenged product andthe expected product. The mixture was concentrated under reducedpressure, and the residue was dissolved in a minimum amount of hot THF.This sample was loaded onto a 5 gm pre-moistened FluoroFlash® SPEcartridge with 80:20 MeOH:H₂O which is set on a vacuum manifold. Thecartridge was eluted with 80:20 MeOH:H₂O, then 100% MeOH to wash offfluorous by-products from the cartridge. The first 2 fractions (2 times8 ml) contained the desired product while the last 2 fractions that areeluted with 100% MeOH contained the fluorous by-products. The fractionswere collected and the solvent evaporated under reduced pressure in aSpeedvac overnight, giving the thiourea in 75% yield as a solid. ¹H NMR,300 MHz, CDCl₃: δ (ppm) 7.75 (br, 1H), 7.47-7.42 (m, 2H), 7.34-7.22 (m,1H), 7.22-7.19 (m, 2H), 6.00 (br, 1H), 3.67-3.60 (m, 2H), 1.60-1.50 (m,2H), 1.39-1.29 (m, 2H), 0.92 (t, J=7.28 Hz, 3H). HRMS: calc'd forC₁₁H₁₆S (M+), 208.1034; found 208.1034 (M+).

[0246] Following the general procedure described above, three substrates(isothiocyanate, isocyanate, and epoxide) were reacted with five aminesto generate a 15-compound library in parallel. The structures of theproducts are shown in Table 5. All product purities were greater than90% by ¹H NMR. TABLE 5 Structures, Yields of Amination Products

Example VII

[0247] Synthesis of Fluorous Trityl

[0248] A solution of ^(t)BuLi (1.7 M in pentane, 20.0 mL) in ether (75mL) was cooled to −78° C. under inert atmosphere.4-(1H,1H,2H,2H-perfluorodecyl)phenylbromide (10.0 g, 0.017 mol) in ether(25 mL) was added at a rate to maintain the internal temperature tobelow −45° C., then allowed to warm to −30° C. for 30 minutes, thencooled back down to −78° C. To the lithiate was added a solution of thebenzophenone (3.10 g) in ether (25 mL) at a rate to maintain theinternal temperature below −45° C. After complete addition, the reactionwas allowed to come to room temperature overnight. The reaction wasquenched with water (50 mL), then acidified to pH=3 with 2 NHCl (25 mL)and separated. The aqueous layer was extracted with ether (2×100 mL),organics combined, washed with brine (100 mL) and dried over MgSO₄. Thesolvent was removed, the crude product was separated via flashchromatography (10% EtOAc in hexanes), and recrystallized frommethanol/water to provide a white crystalline solid (3.0 g, 52%).

[0249] The trityl alcohol (1.0 g, 1.43 mmol) was dissolved in CHCl₃ (50mL) and PCl₃ (4.5 g) was added. The reaction was checked by TLC (10%EtOAc in hexanes), and additional PCl₃ was added to complete thereaction as necessary, with the total reaction time being 8 hr at roomtemperature. The reaction was then quenched with water (5 mL),separated, organic layer dried with MgSO₄ and solvent removed to providethe pure product as an off white crystalline solid (0.84 g, 82% yield).

Example VIII

[0250] Preparation of Fluorous TBD

[0251] To a solution of 1,3,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine(5.6 g) in 80 mL of THF was added 3-(perfluorooctyl)propyl iodide (11.8g) and triethylamine (2.6 mL). The mixture was stirred at 25° C. for 12h. The precipitate was collected by filtration. The solid was mixed with50 mL of 30% NaOH, extracted with EtOAc. The organic layer wasconcentrated to give desired product as a semisolid (3.8 g, 32%).

Example IX

[0252] Preparation of Fluorous Isocyanate

[0253] Preparation of 3-(perfluorooctyl)propionyl Azide:

[0254] Sodium azide (6.0 g) was put in a 250 mL round-bottom flask(2-neck) equipped with a thermometer. H₂O (20 mL) was added to dissolvesodium azide. It was cooled on an ice-water bath. A solution of3-(perfluorooctyl)propionyl chloride (12.9 g) in acetone (25 mL) wasadded dropwise to keep the temperature below 12° C. The mixture wasvigorously stirred for 2 h. Dimethyl ether (100 mL) and water (100 mL)are added, and the mixture was vigorously stirred for 1 min. After theseparation of two layers, the aqueous layer was extracted with ether(2×50 mL). The ether layers were combined, and are washed with water(3×100 mL) and brine. After drying over MgSO₄, the solvent was removedunder vacuum to give a mixture of white solid and liquid (12.0 g) thatwas immediately used for the next reaction.

[0255] Preparation of 3-(perfluorooctyl)ethyl Isocyanate.

[0256] A solution of crude 3-(perfluorooctyl)propionyl azide (12 g) intoluene was put in a 500 mL round-bottom flask equipped with a condenserand a thermometer. The mixture was gradually warmed to 50-55° C. over 1h, and the temperature was maintained at around 55° C. for 2 h. Themixture was then refluxed for 1 h. After cooling, the solvent wasremoved by a rotavap, the residue was distilled under high-vac to givenon-color liquid that solidifies at room temperature.

[0257] Use of Fluorous Isocyanate as an Electrophilic Scavenger in thePreparation of 1-(4-methylbenzyl)-3-phenyl-thiourea.

[0258] To a solution of phenyl isothiocyanate (24 μL) in CH₂Cl₂ (0.5 ml)was added excess amine (30 μL). The resulting solution was stirred at55-60° C. on a sand bath overnight (8-12 h) to ensure completion of thereaction. The reaction was monitored by TLC (30:70 EtOAc:Hexanes). Uponcompletion of the reaction, fluorous isocyanate was added (0.10 g) tothe reaction mixture. Another 1.0-2.0 ml of CH₂Cl₂ was added to thereaction mixture to ensure complete dissolution of the solid. Thereaction mixture was stirred at 60° C. for 2.5 h. TLC showed thepresence of the fluorous scavenger (that was added in excess), thescavenged product and the expected product. The mixture was concentratedunder reduced pressure, and the residue was dissolved in a minimumamount of hot THF. This sample was loaded onto a 5 gm pre-moistenedFluoroFlash® SPE cartridge with 80:20 MeOH:H₂O which is set on a vacuummanifold. The cartridge was eluted with 80:20 MeOH:H₂O, then 100% MeOHto wash off fluorous by-products from the cartridge. The first 2fractions (2 times 8 ml) contained the desired product while the last 2fractions (2 times 8 ml) that are eluted with 100% MeOH contained thefluorous by-products. The fractions were collected and the solventevaporated under reduced pressure in a Speedvac overnight, giving thethiourea in 80% yield as a solid. ¹H NMR, 300 MHz, CDCl₃: δ7.68 (br,1H), 7.41 (t, J=7.94 Hz, 2H), 7.27 (t, J=7.45 Hz, 2H), 7.217.18 (m, 3H),7.14 (d, J=7.77 Hz, 2H), 6.20 (br, 1H), 4.84 (d, J=5.34 Hz, 2H), 2.33(s, 3H). HRMS: calc'd for C₁₅H₁₆N₂S (M+), 256.1034; found 256.1029 (M+).

[0259] Following the general procedure described above, two substrates(isothiocyanate and isocyanate) were reacted with five amines togenerate a 10-compound library in parallel. The structures of theproducts are shown in Table 6. All product purities were greater than90% by ¹H NMR. TABLE 6 Structures, Yields of Amination Products

Example X

[0260] Preparation of 4-(1H, 1H,2H,2H-Perfluorodecyl)benzenesulfonamide

[0261] 1H,1H,2H-perfluorodec-1-ene (8.5 g), 4-bromobenzenesulfoamide(3.0 g), Pd(OAc)₂ (0.13 g), tri-o-tolylphosphine (0.35 g), Bu₄NBr (2.4g), ^(i)Pr₂NEt (8.5 mL) were dissolved in DMF (60 mL), and the mixturewas stirred at 110° C. for 1 d under an nitrogen atmosphere. It was thencooled to room temperature, and DMF was removed under reduced pressure.The crude material was passed through a silica gel column (eluent:hexanes/EtOAc=4:1). The filtrate was concentrated, and it was dissolvedin Et₂O, and then it was treated with charcoal. The charcoal was removedby filtration through a pad of Celite®. The product was purified byfluorous solid-phase extraction with a 20 g FluoroFlash® cartridge(eluent: MeOH/H₂O=70:30 to 100% MeOH). The MeOH fraction wasconcentrated to give the product (1.8 g, 24% yield).

[0262] To a solution of 4-(1H,2H-perfluorodec-1-enyl)benzenesulfonamide(0.11 g) in MeOH (20 mL) was added Pd/C (5 wt % on activated carbon, 33mg) under an nitrogen atmosphere. The mixture was then stirred underhydrogen atmosphere (1 atm) for 20 h at 23° C. The catalyst was removedby filtration through a Celite® pad, and the Celite® was rinsed withEt₂O (100 mL). The filtrate was concentrated to give the product as paleyellow solid (0.10 g, 90% yield). ¹H NMR (270 MHz, CD₃OD) δ7.85 (2H, d,J=8.3 Hz), 7.46 (2H, d, J=8.3 Hz), 4.90 (2H, br s), 3.05-2.98 (2H, m),2.65-2.35 (2H, m); MS APCI negative m/z=632 [M−H].

Example XI

[0263] Preparation of Fluorous Triamine

[0264] In a 50 ml 2-neck flask, 4 angstrom molecular sieves (activatedpowder) (0.10 g) was dried under N₂ flow with a heat gun for 5 min.Cesium hydroxide monohydrate (0.143 g) was added. DMF (15 ml) was added,and the mixture stirred vigorously for 10 min. Diethylenetriamine (0.91ml) was added, and the mixture stirred vigorously for 10 min. Fluorouspropyl iodide (0.50 g) was added portionwise. The mixture was stirredfor under N₂ for 18 h at 25° C. The reaction mixture was extracted withether (3×50 ml). The ether layers were washed with water (2×75 ml) andbrine (1×75 ml). The organic layer was dried over MgSO₄, filtered, andconcentrated. The crude product was taken up in ether. 1 M HCl in ether(1.5 ml) was added. Extracted with H₂O (3×50 ml). The aqueous layer waswashed with 2 N NaOH (50 ml). The product was extracted with ether (3×30ml). The ether layer was concentrated and dried under high vacuum togive product (0.21 g, 44% yield).

[0265] Although the forgoing description has necessarily presented alimited number of embodiments of the invention, those of ordinary skillin the relevant art will appreciate that various changes in thecomponents, details, materials, and process parameters of the examplesthat have been herein described and illustrated in order to explain thenature of the invention may be made by those skilled in the art, and allsuch modifications will remain within the principle and scope of theinvention as expressed herein in the appended claims. It will also beappreciated by those skilled in the art that changes could be made tothe embodiments described above without departing from the broadinventive concept thereof. It is understood, therefore, that thisinvention is not limited to the particular embodiments disclosed, but itis intended to cover modifications that are within the principle andscope of the invention, as defined by the appended claims.

What is claimed is:
 1. A method for increasing the fluorous nature of anorganic compound, comprising: reacting the organic compound with atleast one second compound having the formula:X—CR¹R²—C₆H_(5-m)—[W_(p)(CH₂)_(n)R_(f)]_(m) to create a first fluoroustagged organic compound, wherein R_(f) is a fluorous group, X isselected from the group consisting of a leaving group, a nucleophilicgroup and an electrophilic group, R¹ and R² are independently, the sameor different, one of hydrogen, linear alkyl, branched alkyl, phenyl,C₆H_(5-q)(W′)_(q), C₆H_(5-m′)[W_(p′)(CH₂)_(n′)R_(f)]_(m′) andC₆H_(5-m″)[W_(p″)(CH₂)_(n″)R_(f)]_(m″), m, m′ and m″ are each integersfrom 1 to 5, n, n′ and n″ are each integers from 0 to 5, p, p′ and p″each have a value of 0 or 1, q is an integer from 0 to 5, W is agrouping of atoms selected from the group consisting of O, S, NR³,CR⁴R⁵, and SiR⁶R⁷, wherein when W is SiR⁶R⁷ and R¹ and R² are eachhydrogen, X is not one of Br, N-imidazolyl and —OH, and W′ is a groupingof atoms selected from the group consisting of OR⁸, SR⁹, NR¹⁰R¹¹,CR¹²R¹³R¹⁴, and SiR¹⁵R¹⁶R¹⁷, wherein R³, R⁴, R⁵, R⁸, R⁹, R¹⁰, R¹¹, R¹²,R¹³, and R¹⁴ are independently, the same or different, one of hydrogen,linear alkyl, branched alkyl, aryl, benzyl and —(CH₂)_(n′41) R_(f) andR⁶, R⁷, R¹⁵, R¹⁶, and R¹⁷ are independently, the same or different, oneof linear alkyl, branched alkyl, aryl, benzyl and —(CH₂)_(n′″)R_(f),wherein n′″ in an integer from 0 to 5, the organic compound having atleast one functional group reactive with group X on the second compoundforming at least one chemical bond between the organic compound and thesecond compound resulting in the first fluorous tagged organic compoundwherein the fluorous nature of the first fluorous tagged organiccompound is increased relative to the organic compound to enableseparation of the first fluorous tagged organic compound from at leastone other compound by using a fluorous separation technique.
 2. Themethod of claim 1, further comprising reducing the fluorine content of asecond fluorous tagged organic compound, wherein the second fluoroustagged organic compound is produced from subsequent chemicaltransformations on the first fluorous tagged organic compound.
 3. Themethod of claim 2, wherein the fluorine content of the second fluoroustagged organic compound is reduced by removing at least one grouping ofatoms having a structure selected from the group consisting of:—CR¹R²—C₆H_(5-m)—[W_(p)(CH₂)_(n)R_(f)]_(m),—C₆H_(5-m)—[W_(p)(CH₂)_(n)R_(f)]_(m), —[W_(p)(CH₂)_(n)R_(f)]_(m),(CH₂)_(n)R_(f), and R_(f) from the second fluorous tagged organiccompound.
 4. The method of claim 1 wherein X is a leaving group selectedfrom the group consisting of a halide, a methane sulfonate, ap-toluenesulfonate, a trifluoromethanesulfonate and R¹⁸SO₃—, wherein R¹⁸is one of linear alkyl, branched alkyl, aryl, benzyl, and—(CH₂)_(n″″)R_(f), wherein n″″ in an integer from 0 to
 5. 5. The methodof claim 1 wherein X is a nucleophilic group selected from the groupconsisting of —OH, —NH₂, —NHR¹⁹, —NR¹⁹R²⁰, —NHC(═NH)NH₂, —SH, —SR¹⁹,—NH(CH₂)_(n″″)NH₂, and —NH(CH₂)_(n″″)N((CH₂)_(n″″)NH₂)₂, wherein n″″ isan integer from 1 to 5, and R¹⁹ and R²⁰ are independently, the same ordifferent, one of a linear alkyl, a branched alkyl, an aryl and a benzylgroup.
 6. The method of claim 1 wherein X is an electrophilic groupcomprising —NCZ, wherein Z is one of oxygen and sulfur.
 7. The method ofclaim 1 wherein R_(f) is a fluorous group selected from the groupconsisting of a perfluorocarbon, a fluorohydrocarbon, a fluorinatedether and a fluorinated amine.
 8. The method of claim 1 wherein X is aleaving group and R¹ and R² are each hydrogen.
 9. The method of claim 1wherein X is a leaving group and R¹ and R² are independently, the sameor different, one Of C₆H_(5-m′)[W_(p′)(CH₂)_(n′)R_(f)]_(m′) andC₆H_(5-m″)[W_(p″)(CH₂)_(n″)R_(f)]_(m″).
 10. The method of claim 1wherein X is —SH.
 11. The method of claim 1 wherein X is one of NR²¹R²²and NR²¹R²²R²³⁺Y⁻, wherein R²¹, R²² and R²³ are independently, the sameor different, one of a hydrogen, a linear alkyl, a branched alkyl and abenzyl group and Y is a counter anion selected from the group consistingof Cl⁻, Br⁻, I⁻ and CO₃ ²⁻.
 12. The method of claim 1 wherein X is —OH,R¹ is hydrogen and R² is one of H and C₆H_(5-q)(W′)_(q).
 13. The methodof claim 1 wherein X is —NH₂, R¹ is hydrogen and R² isC₆H_(5-q)(W′)_(q).
 14. The method of claim 1 wherein X is—NH(CH₂)_(n″″)NH₂.
 15. The method of claim 1 wherein X is—NH(CH₂)_(n″″)N((CH₂)_(n″″)NH₂)₂.
 16. The method of claim 1 wherein X is—NHC(═N)NH₂.
 17. The method of claim 1 wherein X is —SH and R¹ and R²are each hydrogen.
 18. The method of claim 1 wherein X is —SR²⁴, whereinR²⁴ is one of a linear alkyl, a branched alkyl, an aryl, and a benzylgroup.
 19. The method of claim 1 wherein X is —NCZ, wherein Z is one ofO and S, and R¹ and R² are each hydrogen.
 20. A method for increasingthe fluorous nature of an organic compound, comprising: reacting theorganic compound with at least one second compound having the formula:XCO₂CH₂R_(d) to create a first fluorous tagged organic compound, whereinX is a leaving group and R_(d) is selected from the group consisting of:a) —CH═CH—(CH₂)_(n)R_(f),

c) —C₆H_(5-m″)[W_(p)(CH₂)_(n)R_(f)]_(m″), wherein R_(f) and R_(f)′ areeach fluorous groups, m is an integer from 1 to 4, m′ is an integer from0 to 4, m″ is an integer from 1 to 5, n and n′ are each integers from 0to 5, p and p′ each have a value of 0 or 1, and W and W′ are groupingsof atoms each selected from the group consisting of O, S, NR²⁵, CR²⁶R²⁷,and SiR²⁸R²⁹, wherein R²⁵, R²⁶ and R²⁷ are independently, the same ordifferent, one of hydrogen, linear alkyl, branched alkyl, aryl, benzyland —(CH₂)_(n)R_(f), and R²⁸ and R²⁹ are independently, the same ordifferent, one of linear alkyl, branched alkyl, aryl, benzyl and—(CH₂)_(n)R_(f), the organic compound having at least one functionalgroup reactive with group X on the second compound forming at least onechemical bond between the organic compound and the second compoundresulting in the first fluorous tagged organic compound wherein thefluorous nature of the first fluorous tagged organic compound isincreased relative to the organic compound to enable separation of thefirst fluorous tagged organic compound from at least one other compoundby using a fluorous separation technique.
 21. The method of claim 20,further comprising reducing the fluorine content of a second fluoroustagged organic compound, wherein the second fluorous tagged organiccompound is produced from subsequent chemical transformations on thefirst fluorous tagged organic compound.
 22. The method of claim 21,wherein the fluorine content of the second fluorous tagged organiccompound is reduced by removing at least one grouping of atoms having astructure selected from the group consisting of: —CO₂CH₂R_(d),—OCH₂R_(d), R_(d), and R_(f) from the second fluorous tagged organiccompound.
 23. The method of claim 20 wherein X is a leaving groupselected from the group consisting of a halide, —N₃, —CN, —OR, —ONH₂,—ONHR³⁰, —ONR², —O₂CR³⁰, —O₂COR³⁰, —O₂CNR³⁰ ₂, —SR³⁰, —OC(S)R³⁰,R³⁰CS₂—, —SC(O)SR³⁰, —SCS₂R³⁰, —OC(O)SR³⁰, —OC(S)OR³⁰, —SC(S)OR³⁰,R³⁰SO₂—, R³⁰SO₃—, R³⁰OSO₂—, R³⁰OSO₃—, R³⁰PO₃—, R³⁰PO₃—, an N-imidazolylgroup, an N-triazolyl group, an N-benzotriazolyl group, abenzotriazolyloxy group, an imidazolyloxy group, an N-imidazolinonegroup, an N-imidazolone group, an N-imidazolinethione group, anN-succinimidyl group, an N-phthalimidyl group, an N-succinimidyloxygroup, an N-phthalimidyloxy group, —ON═C(CN)R³⁰, and a 2-pyridyloxygroup, wherein R³⁰ is one of linear alkyl, branched alkyl, aryl, benzyl,and —(CH₂)_(n″)R_(f), wherein n″ in an integer from 0 to
 5. 24. Themethod of claim 20 wherein R_(f) and R_(f′) are independently, the sameor different, a fluorous group selected from the group consisting of aperfluorocarbon, a fluorohydrocarbon, a fluorinated ether and afluorinated amine.
 25. The method of claim 20 wherein R_(d) is—CH═CH—(CH₂)_(n)R_(f).
 26. The method of claim 20 wherein R_(d) is


27. The method of claim 20 wherein R_(d) is—C₆H_(5-m″)[W_(p)(CH₂)_(n)R_(f)]_(m″).
 28. A method for increasing thefluorous nature of an organic compound, comprising: reacting the organiccompound with at least one fluorous nitrogen containing compound havingthe formula: R³¹R³²N(CH₂)_(n)R_(f) to create a first fluorous taggedorganic compound, wherein n is an integer from 0 to 5, R_(f) is afluorous group, and R³¹R³² is selected from the group consisting of: a)—(CH₂)_(m)W(CH₂)_(m′)—, wherein m and m′ are each integers between 2 and4, W is one of CH₂, O, S, NH, and NR³³, wherein R³³ is one of a linearalkyl, a branched alkyl and a benzyl group,

 wherein m″, and m′″ are each integers from 0 to 3,

 wherein W′ is a grouping of atoms selected from the group consisting ofO, S, NR³⁴, CR³⁵R³⁶, and SiR³⁷R³⁸, p has a value of 0 or 1, n′ is aninteger from 0 to 5, m″″ is an integer from 0 to 4, R³⁴, R³⁵, and R³⁶are independently, the same or different, one of hydrogen, linear alkyl,branched alkyl, aryl, benzyl and —(CH₂)_(n)R_(f), and R³⁷ and R³⁸ areindependently, the same or different, one of linear alkyl, branchedalkyl, aryl, benzyl and —(CH₂)_(n)R_(f), d) alkyl and pyridyl, e)hydrogen and —(CH₂)_(n″)NH₂, wherein n″ is an integer from 1 to 5, f)hydrogen and —(CH₂)_(n″)N[(CH₂)_(n″)NH₂]₂, and g) —(CH₂)_(n′″)OH, and—(CH₂)_(n″″)OH, wherein n′″ and n″″ are each integers between 1 and 5,the organic compound having at least one functional group reactive withat least one N or —OH group on the second compound forming at least onechemical bond between the organic compound and the second compoundresulting in the first fluorous tagged organic compound wherein thefluorous nature of the first fluorous tagged organic compound isincreased relative to the organic compound to enable separation of thefirst fluorous tagged organic compound from at least one other compoundby using a fluorous separation technique.
 29. The method of claim 28,further comprising reducing the fluorine content of a second fluoroustagged organic compound, wherein the second fluorous tagged organiccompound is produced from subsequent chemical transformations on thefirst fluorous tagged organic compound.
 30. The method of claim 29,wherein the fluorine content of the second fluorous tagged organiccompound is reduced by removing at least one grouping of atoms having astructure selected from the group consisting of: R³¹R³²N(CH₂)_(n)R_(f),—N(CH₂)_(n)R_(f), —(CH₂)_(n)R_(f), and R_(f) from the second fluoroustagged organic compound.
 31. The method of claim 28 wherein R_(f) is afluorous group selected from the group consisting of a perfluorocarbon,a fluorohydrocarbon, a fluorinated ether and a fluorinated amine. 32.The method of claim 28 wherein the fluorous nitrogen containing compoundis a cyclic amine.
 33. The method of claim 28 wherein R³¹R³² is—(CH₂)_(m)W(CH₂)_(m′)—.
 34. The method of claim 28 wherein R³¹R³² is


35. The method of claim 28 wherein R³¹R³² is


36. The method of claim 28 wherein R³¹ is one of a linear alkyl and abranched alkyl, and R³² is pyridyl.
 37. The method of claim 28 whereinR³¹ is hydrogen and R³² is —(CH₂)_(n) NH₂.
 38. The method of claim 28wherein R³¹ is hydrogen and R³² is —(CH₂)_(n″)N[(CH₂)_(n″)NH₂]₂.
 39. Themethod of claim 28 wherein R³¹ is —(CH₂)_(n′″)OH, and R³² is—(CH₂)_(n″″)OH.
 40. A method for increasing the fluorous nature of anorganic compound, comprising: reacting the organic compound with atleast one second compound having the formula:X—C₆H_(5-m)—[W_(p)(CH₂)_(n)R_(f)]_(m) to create a first fluorous taggedorganic compound, wherein R_(f) is a fluorous group, m is an integerfrom 1 to 5, n is an integer from 0 to 5, p has a value of 0 or 1, and Wis a grouping of atoms selected from the group consisting of O, S, NR³⁹,CR⁴⁰R⁴¹, and SiR⁴²R⁴³, wherein when W is O, X is a grouping of atomsselected from the group consisting of —SO₂NHNH₂, —CHO when p is 1, —SH,—(CH₂)_(n′)SH, —C(═NR^(B))C₆H₄Y, —C(═O)CH₂C(═O)R⁴⁴, —COCl, —SO₂Cl, —OH,—NCZ, and —SO₃H, wherein when W is one of S, NR³⁹, CR⁴⁰R⁴¹, andSiR⁴²R⁴³, X is a grouping of atoms selected from the group consisting of—SO₂NH₂, —SO₂NHNH₂, —CHO when p is 1, —SH, —(CH₂)_(n″)SH,—C(═NR^(B))C₆H₄Y, —C(═O)CH₂C(═O)R⁴⁴, —COCl, —SO₂Cl, —OH, —NCZ, and—SO₃H, wherein n′ is an integer from 2 to 5, r is an integer from 0 to2, Z is one of O and S, Y is one of an electron withdrawing group, ahydrogen and an alkyl group, R^(B) is one of hydrogen, alkyl, aryl andhydroxyl, R⁴⁴ is one of linear alkyl, branched alkyl and benzyl, R³⁹,R⁴⁰ and R⁴¹ are independently, the same or different, one of hydrogen,linear alkyl, branched alkyl, aryl, benzyl and —(CH₂)_(n)R_(f), and R⁴²and R⁴³ are independently, the same or different, one of linear alkyl,branched alkyl, aryl, benzyl and —(CH₂)_(n)R_(f), the organic compoundhaving at least one functional group reactive with group X on the secondcompound forming at least one chemical bond between the organic compoundand the second compound resulting in the first fluorous tagged organiccompound wherein the fluorous nature of the first fluorous taggedorganic compound is increased relative to the organic compound to enableseparation of the first fluorous tagged organic compound from at leastone other compound by using a fluorous separation technique.
 41. Themethod of claim 40, further comprising reducing the fluorine content ofa second fluorous tagged organic compound, wherein the second fluoroustagged organic compound is produced from subsequent chemicaltransformations on the first fluorous tagged organic compound.
 42. Themethod of claim 41, wherein the fluorine content of the second fluoroustagged organic compound is reduced by removing at least one grouping ofatoms having a structure selected from the group consisting of:—C₆H_(5-m)—[W_(p)(CH₂)_(n)R_(f)]_(m), —[W_(p)(CH₂)_(n)R_(f)]_(m),—(CH₂)_(n)R_(f), and R_(f) from the second fluorous tagged organiccompound.
 43. The method of claim 40 wherein R_(f) is a fluorous groupselected from the group consisting of a perfluorocarbon, afluorohydrocarbon, a fluorinated ether and a fluorinated amine.
 44. Themethod of claim 40 wherein X is —SO₂NH₂ and W is one of S, NR³⁹,CR⁴⁰R⁴¹, and SiR⁴²R⁴³.
 45. The method of claim 40 wherein X is—SO₂NHNH₂.
 46. The method of claim 40 wherein X is —CHO and p is
 1. 47.The method of claim 40 wherein X is —SH.
 48. The method of claim 40wherein X is CH₂)_(n′)SH.
 49. The method of claim 40 wherein X is—C(═NR^(B))C₆H₄Y, wherein Y is one of an electron withdrawing group, ahydrogen and an alkyl group, and R^(B) is one of hydrogen, alkyl, aryland hydroxyl.
 50. The method of claim 49 wherein Y is an electronwithdrawing group selected from the group consisting of —NO₂, —CN, —Fand —Cl.
 51. The method of claim 40 wherein X is —C(═O)CH₂C(═O)R⁴⁴. 52.The method of claim 40 wherein X is —COCl.
 53. The method of claim 40wherein X is —SO₂Cl.
 54. The method of claim 40 wherein X is —OH. 55.The method of claim 40 wherein X is —NCZ, wherein Z is one of O and S.56. The method of claim 40 wherein X is —SO₃H.
 57. A method forincreasing the fluorous nature of an organic compound, comprising:reacting the organic compound with at least one second compound havingthe formula: X—(CH₂)_(n)R_(f) to create a first fluorous tagged organiccompound, wherein R_(f) is a fluorous group, n is an integer from 0 to5, and X is a grouping of atoms selected from the group consisting of—C(CH₃)₂COCl, —CR⁴⁵R⁴⁶ SH, —CR⁴⁵R⁴⁶SR⁴⁷, —SO₂Cl, —OC(═O)NHNH₂,—NHC(═NH)NH₂, —SO₂NH₂, —SO₂NHNH₂, —NCZ, -maleimide, -α-succinicanhydride, and —COCH₂COR⁴⁸, wherein Z is one of O and S, and R⁴⁵, R⁴⁶,R⁴⁷, and R⁴⁸ are independently, the same or different, selected from thegroup consisting of hydrogen, linear alkyl, branched alkyl, benzyl, and—(CH₂)_(n)R_(f), the organic compound having at least one functionalgroup reactive with group X on the second compound forming at least onechemical bond between the organic compound and the second compoundresulting in the first fluorous tagged organic compound wherein thefluorous nature of the first fluorous tagged organic compound isincreased relative to the organic compound to enable separation of thefirst fluorous tagged organic compound from at least one other compoundby using a fluorous separation technique.
 58. The method of claim 57,further comprising reducing the fluorine content of a second fluoroustagged organic compound, wherein the second fluorous tagged organiccompound is produced from subsequent chemical transformations on thefirst fluorous tagged organic compound.
 59. The method of claim 58,wherein the fluorine content of the second fluorous tagged organiccompound is reduced by removing at least one grouping of atoms having astructure selected from the group consisting of: X′(CH₂)_(n)R_(f),—(CH₂)_(n)R_(f), and R_(f) from the second fluorous tagged organiccompound, wherein X′ is one of COC(CH₃)₂—, SO₂— and NH₂NHCO₂—.
 60. Themethod of claim 57 wherein R_(f) is a fluorous group selected from thegroup consisting of a perfluorocarbon, a fluorohydrocarbon, afluorinated ether and a fluorinated amine.
 61. The method of claim 57wherein X is —C(CH₃)₂COCl.
 62. The method of claim 57 wherein X is—CR⁴⁵R⁴⁶SH.
 63. The method of claim 57 wherein X is —CR⁴⁵R⁴⁶SR⁴⁷. 64.The method of claim 57 wherein X is —SO₂Cl.
 65. The method of claim 57wherein X is —OC(═O)NHNH₂.
 66. The method of claim 57 wherein X is—NHC(═NH)NH₂.
 67. The method of claim 57 wherein X is —SO₂NH₂.
 68. Themethod of claim 57 wherein X is —SO₂NHNH₂.
 69. The method of claim 57wherein X is —NCZ, wherein Z is one of O and S.
 70. The method of claim57 wherein X is -maleimide.
 71. The method of claim 57 wherein X is-α-succinic anhydride.
 72. The method of claim 57 wherein X is—COCH₂COR⁴⁸.
 73. A compound for increasing the fluorous nature of anorganic compound, said compound having the formula:X—CR¹R²—C₆H_(5-m)—[W_(p)(CH₂)_(n)R_(f)]_(m) wherein R_(f) is a fluorousgroup, X is selected from the group consisting of a leaving group, anucleophilic group and an electrophilic group, R¹ and R² areindependently, the same or different, one of a hydrogen, a linear alkyl,a branched alkyl, a phenyl, an aryl, C₆H_(5-q)(W′)_(q),C₆H_(5-m′)[W_(p′)(CH₂)_(n′)R_(f)]_(m′) andC₆H_(5-m″)[W_(p″)(CH₂)_(n″)R_(f)]_(m″), m, m′ and m″ are each integersfrom 1 to 5, n, n′ and n″ are each integers from 0 to 5, p, p′ and p″each have a value of 0 or 1, q is an integer from 0 to 5, W is agrouping of atoms selected from the group consisting of O, S, NR³,CR⁴R⁵, and SiR⁶R⁷, wherein when W is SiR⁶R⁷ and R¹ and R² are eachhydrogen, X is not one of Br, N-imidazolyl and —OH, and W′ is a groupingof atoms selected from the group consisting of OR⁸, SR⁹, NR¹⁰R¹¹,CR¹²R¹³R¹⁴, and SiR¹⁵R¹⁶R¹⁷, wherein R³, R⁴, R⁵, R⁶, R⁸, R⁹, R¹⁰, R¹¹,R¹², R¹³, and R¹⁴ are independently, the same or different, one ofhydrogen, linear alkyl, branched alkyl, aryl, benzyl and—(CH₂)_(n′″)R_(f) and R⁶, R⁷, R¹⁵, R¹⁶, and R¹⁷ are independently, thesame or different, one of linear alkyl, branched alkyl, aryl, benzyl and—(CH₂)_(n′″)R_(f), wherein n′″ in an integer from 0 to
 5. 74. Thecompound of claim 73 wherein X is a leaving group selected from thegroup consisting of a halide, a methane sulfonate, a p-toluenesulfonate,a trifluoromethanesulfonate and R¹⁸SO₃—, wherein R¹⁸ is one of linearalkyl, branched alkyl, aryl, benzyl, and —(CH₂)_(n″″)R_(f), wherein n″″in an integer from 0 to
 5. 75. The compound of claim 73 wherein X is anucleophilic group selected from the group consisting of —OH, —OR¹⁹,—NH₂, —NHR¹⁹, —NR¹⁹R²⁰, —NHC(═NH)NH₂, —SH, —SR¹⁹, —NH(CH₂)_(n″″)NH₂, and—NH(CH₂)_(n″″)N((CH₂)_(n″″)NH₂)₂, wherein n is an integer from 1 to 5,and R¹⁹ and R²⁰ are independently, the same or different, one of alinear alkyl, a branched alkyl, an aryl and a benzyl group.
 76. Thecompound of claim 73 wherein X is the electrophilic group comprising—NCZ, wherein Z is one of oxygen and sulfur.
 77. The compound of claim73 wherein R_(f) is a fluorous group selected from the group consistingof a perfluorocarbon, a fluorohydrocarbon, a fluorinated ether and afluorinated amine.
 78. The compound of claim 73 wherein X is a leavinggroup and R¹ and R² are each hydrogen.
 79. The compound of claim 73wherein X is a leaving group and R¹ and R² are independently, the sameor different, one of C₆H_(5-m′)[W_(p′)(CH₂)_(n′)R_(f)]_(m′) andC₆H_(5-m″)[W_(p″)(CH₂)_(n″)R_(f)]_(m ″).
 80. The compound of claim 73wherein X is —SH.
 81. The compound of claim 73 wherein X is one ofNR²¹R²² and NR²¹R²²R²³⁺Y³¹, wherein R²¹, R²² and R²³ are independently,the same or different, one of a hydrogen, a linear alkyl, a branchedalkyl and a benzyl group and Y is a counter anion selected from thegroup consisting of Cl⁻, Br⁻, I⁻ and CO₃ ²⁻.
 82. The compound of claim73 wherein X is —OH, R¹ is hydrogen and R² is C₆H_(5-q)(W′)_(q).
 83. Thecompound of claim 73 wherein X is —NH₂, R¹ is hydrogen and R² isC₆H_(5-q)(W′)_(q).
 84. The compound of claim 73 wherein X is—NH(CH₂)_(n′″)NH₂.
 85. The compound of claim 73 wherein X is—NH(CH₂)_(n″″)N((CH₂)_(n″″)NH₂)₂.
 86. The compound of claim 73 wherein Xis —NHC(═N)NH₂.
 87. The compound of claim 73 wherein X is —SH and R¹ andR² are each hydrogen.
 88. The compound of claim 73 wherein X is SR²⁴,wherein R²⁴ is one of a linear alkyl, a branched alkyl, an aryl, and abenzyl group.
 89. The compound of claim 73 wherein X is —NCZ, wherein Zis one of O and S and R¹ and R² are each hydrogen.
 90. A compound forincreasing the fluorous nature of an organic compound, the compoundhaving the formula: XCO₂CH₂R_(d) wherein X is a leaving group and R_(d)is selected from the group consisting of: a) —CH═CH—(CH₂)_(n)R_(f),

c) —C₆H_(5-m″)[W_(p)(CH₂)_(n)R_(f)]_(m″), wherein R_(f) and R_(f)′ arefluorous groups, m is an integer from 1 to 4, m′ is an integer from 0 to4, m″ is an integer from 1 to 5, n and n′ are each integers from 0 to 5,p and p′ each have a value of 0 or 1, and W and W′ are groupings ofatoms each selected from the group consisting of O, S, NR²⁵, CR²⁶R²⁷ andSiR²⁸R²⁹, wherein R²⁵, R²⁶ and R²⁷ are independently, the same ordifferent, one of hydrogen, linear alkyl, branched alkyl, aryl, benzyland —(CH₂)_(n)R_(f), and R²⁸ and R²⁹ are independently, the same ordifferent, one of linear alkyl, branched alkyl, aryl, benzyl and—(CH₂)_(n)R_(f).
 91. The compound of claim 90 wherein X is a leavinggroup selected from the group consisting of a halide, —N₃, —CN, —OR³⁰,—ONH₂, —ONHR³⁰, —ONR³⁰ ₂, —O₂CR³⁰, —O₂COR³⁰, —O₂CNR³⁰ ₂, —SR³⁰,—OC(S)R³⁰, R³⁰CS₂—, —SC(O)SR³⁰, —SCS₂R³⁰, —OC(O)SR³⁰, —OC(S)OR³⁰,—SC(S)OR³⁰, R³⁰SO₂—, R³⁰SO₃—, R³⁰OSO₂—, R³⁰OSO₃—, R³⁰PO₃—, R³⁰PO₃—, anN-imidazolyl group, an N-triazolyl group, an N-benzotriazolyl group, abenzotriazolyloxy group, an imidazolyloxy group, an N-imidazolinonegroup, an N-imidazolone group, an N-imidazolinethione group, anN-succinimidyl group, an N-phthalimidyl group, an N-succinimidyloxygroup, an N-phthalimidyloxy group, —ON═C(CN)R³⁰, and a 2-pyridyloxygroup, wherein R³⁰ is one of linear alkyl, branched alkyl, aryl, benzyl,and —(CH₂)_(n″)R_(f), wherein n″ in an integer from 0 to
 5. 92. Thecompound of claim 90 wherein R_(f) and R_(f)′ are independently, thesame or different, a fluorous group selected from the group consistingof a perfluorocarbon, a fluorohydrocarbon, a fluorinated ether and afluorinated amine.
 93. The compound of claim 90 wherein R_(d) is—CH═CH—(CH₂)_(n)R_(f).
 94. The compound of claim 90 wherein R_(d) is


95. The compound of claim 90 wherein R_(d) is—C₆H_(5-m″)[W_(p)(CH₂)_(n)R_(f)]_(m″).
 96. A fluorous nitrogencontaining compound having the formula: R³¹R³²N(CH₂)_(n)R_(f) wherein nis an integer from 0 to 5, R_(f) is a fluorous group, and R³¹R³² isselected from the group consisting of: a) —(CH₂)_(m)W(CH₂)_(m′)—,wherein m and m′ are each integers between 2 and 4, W is one of CH₂, O,S, NH, and NR³³, wherein R³³ is one of a linear alkyl, a branched alkyland a benzyl group,

 wherein m″ and m′″ are each integers from 0 to 3,

 wherein W′ is a grouping of atoms selected from the group consisting ofO, S, NR³⁴, CR³⁵R³⁶, SiR³⁷R³⁸, p has a value of 0 or 1, n′ is an integerfrom 0 to 5, m″″ is an integer from 0 to 4, R³⁴, R³⁵, and R³⁶ areindependently, the same or different, one of hydrogen, linear alkyl,branched alkyl, aryl, benzyl and —(CH₂)_(n)R_(f), and R³⁷ and R³⁸ areindependently, the same or different, one of linear alkyl, branchedalkyl, aryl, benzyl and —(CH₂)_(n)R_(f), d) alkyl and pyridyl, e)hydrogen and CH₂)_(n″)NH₂, wherein n″ is an integer from 1 to 5, f)hydrogen and —(CH₂)_(n″)N[(CH₂)_(n″)NH₂]₂, and g) —(CH₂)_(n′″)OH, and—(CH₂)_(n″″)OH, wherein n′″ and n″″ are each integers between 1 and 5.97. The compound of claim 96 wherein R_(f) is a fluorous group selectedfrom the group consisting of a perfluorocarbon, a fluorohydrocarbon, afluorinated ether and a fluorinated amine.
 98. The compound of claim 96wherein the fluorous nitrogen containing compound is a cyclic amine. 99.The compound of claim 96 wherein R³¹R³² is —(CH₂)_(m)W(CH₂)_(m′)—. 100.The compound of claim 96 wherein R³¹R³² is


101. The compound of claim 96 wherein R³¹R³² is


102. The compound of claim 96 wherein R³¹ is one of linear alkyl andbranched alkyl, and R³² is pyridyl.
 103. The compound of claim 96wherein R³¹ is hydrogen and R³² is —(CH₂)_(n″)NH₂.
 104. The compound ofclaim 96 wherein R³¹ is hydrogen and R³² is—(CH₂)_(n″)N[(CH₂)_(n″)NH₂]₂.
 105. The compound of claim 96 wherein R³¹is —(CH₂)_(n′″)OH, and R³² is —(CH₂)_(n″″)OH.
 106. A compound forincreasing the fluorous nature of an organic compound, the compoundhaving the formula: X—C₆H_(5-m)—[W_(p)(CH₂)_(n)R_(f)]_(m) wherein R_(f)is a fluorous group, m is an integer from 1 to 5, n is an integer from 0to 5, p has a value of 0 or 1, and W is a grouping of atoms selectedfrom the group consisting of O, S, NR³⁹, CR⁴⁰R⁴¹, and SiR⁴²R⁴³ whereinwhen W is O, X is a grouping of atoms selected from the group consistingof —SO₂NHNH₂, —CHO when p is 1, —SH, —CH₂)_(n′)SH, —C(═NR^(B))C₆H₄Y,—C(═O)CH₂C(═O)R⁴⁴, wherein when W is one of S, NR³⁹, CR⁴⁰R⁴¹, andSiR⁴²R⁴³, X is a grouping of atoms selected from the group consistingof-SO₂NH₂, —SO₂NHNH₂, —CHO when p is 1, —SH, —(CH₂)_(n′)SH,—C(═NR^(B))C₆H₄Y, and —C(═O)CH₂C(═O)R⁴⁴, wherein Y is one of an electronwithdrawing group, a hydrogen and an alkyl group, R^(B) is one ofhydrogen, alkyl, aryl and hydroxyl, R⁴⁴ is one of linear alkyl, branchedalkyl and benzyl, R³⁹, R⁴⁰ and R⁴¹ are independently, the same ordifferent, one of hydrogen, linear alkyl, branched alkyl, aryl, benzyland —(CH₂)_(n)R_(f), and R⁴² and R⁴³ are independently, the same ordifferent, one of linear alkyl, branched alkyl, aryl, benzyl and—(CH₂)_(n)R_(f).
 107. The compound of claim 106 wherein R_(f) is afluorous group selected from the group consisting of a perfluorocarbon,a fluorohydrocarbon, a fluorinated ether and a fluorinated amine. 108.The compound of claim 106 wherein X is —SO₂NH₂ and W is one of S, NR³⁹,CR⁴⁰R⁴¹, and SiR⁴²R⁴³.
 109. The compound of claim 106 wherein X is—SO₂NHNH₂.
 110. The compound of claim 106 wherein X is —CHO and p is 1.111. The compound of claim 106 wherein X is —SH.
 112. The compound ofclaim 106 wherein X is —(CH₂)_(n′)SH.
 113. The compound of claim 106wherein X is —C(═NR^(B))C₆H₄Y, wherein Y is one of an electronwithdrawing group, a hydrogen and an alkyl group, and R^(B) is one ofhydrogen, alkyl, aryl and hydroxyl.
 114. The compound of claim 113wherein Y is an electron withdrawing group selected from the groupconsisting of —NO₂, —CN, —F and —Cl.
 115. The compound of claim 106wherein X is —C(═O)CH₂C(═O)R⁴⁴.
 116. A compound for increasing thefluorous nature of an organic compound, the compound having the formula:X—(CH₂)_(n)R_(f) wherein R_(f) is a fluorous group, n is an integer from0 to 5, and X is —C(CH₃)₂COCl.
 117. The compound of claim 116 whereinR_(f) is a fluorous group selected from the group consisting of aperfluorocarbon, a fluorohydrocarbon, a fluorinated ether and afluorinated amine.
 118. A compound for increasing the fluorous nature ofan organic compound, the compound having the structure selected from thegroup consisting of:

wherein X and X′ are each leaving groups, R_(f), R_(f)′, and R_(f)″ areeach fluorous groups, R_(f)′″ is a perfluoroalkyl group of 8 to 16carbon atoms, m is an integer from 1 to 5, m′, m″, n, n′, and n″ areeach integers from 0 to 5, m′″ is an integer from 0 to 4, p, p′, and p″each have a value of 0 or 1, and W, W′ and W″ are each a grouping atomsof selected from the group consisting of O, S, NR⁴⁹, CR⁵⁰R⁵¹, andSiR⁵²R⁵³, wherein R⁴⁹, R⁵⁰, and R⁵¹ are independently, the same ordifferent, one of hydrogen, linear alkyl, branched alkyl, aryl, benzyland —(CH₂)_(n′″)R_(f), R⁵² and R⁵³ are independently, the same ordifferent, one of hydrogen, linear alkyl, branched alkyl, aryl, benzyland —(CH₂)_(n′″)R_(f) and n′″ is an integer from 0 to
 5. 119. Thecompound of claim 118 wherein X is a leaving group selected from thegroup consisting of a halide, —N₃, —CN, —OR⁵⁴, —ONH₂, —ONHR⁵⁴, —ONR⁵⁴ ₂,—O₂CR⁵⁴, —O₂COR⁵⁴, —O₂CNR⁵⁴ ₂, —SR⁵⁴, —OC(S)R⁵⁴, R⁵⁴CS₂—, —SC(O)SR⁵⁴,—SCS₂R⁵⁴, —OC(O)SR⁵⁴, —OC(S)OR⁵⁴, —SC(S)OR⁵⁴, R⁵⁴SO₂—, R⁵⁴SO₃—,R⁵⁴OSO₂—, R⁵⁴OSO₃—, R⁵⁴PO₃—, R⁵⁴OPO₃—, an N-imidazolyl group, anN-triazolyl group, an N-benzotriazolyl group, a benzotriazolyloxy group,an imidazolyloxy group, an N-imidazolinone group, an N-imidazolonegroup, an N-imidazolinethione group, an N-succinimidyl group, anN-phthalimidyl group, an N-succinimidyloxy group, an N-phthalimidyloxygroup, —ON═C(CN)R⁵⁴, and a 2-pyridyloxy group, wherein R⁵⁴ is one oflinear alkyl, branched alkyl, aryl, benzyl, and —(CH₂)_(n″)R_(f),wherein n″″ in an integer from 0 to
 5. 120. The compound of claim 118wherein X′ is a leaving group selected from the group consisting of ahalide, a methane sulfonate, a p-toluenesulfonate, atrifluoromethanesulfonate and R¹⁸SO₃—, wherein R¹⁸ is one of linearalkyl, branched alkyl, aryl, benzyl, and —(CH₂)_(n″″)R_(f), wherein n″″in an integer from 0 to 5.